Novel Imidazole Amines as Modulators of Kinase Activity

ABSTRACT

The invention provides novel imidazole amine compounds according to Formula (I) and Formula (II) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

FIELD OF THE INVENTION

The invention relates to a series of imidazole amine compounds that areuseful in the treatment of hyperproliferative diseases, such as cancer,in mammals. Also encompassed by the present invention is the use of suchcompounds in the treatment of hyperproliferative diseases in mammals,especially humans, and pharmaceutical compositions containing suchcompounds.

SUMMARY OF THE RELATED ART

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

Protein kinase 70S6K, the 70 kDa ribosomal protein kinase p70S6K (alsoknown as SK6, p70/p85 S6 kinase, p70/p85 ribosomal S6 kinase andp70S6K), is a member of the AGC subfamily of protein kinases. p70S6K isa serine-threonine kinase that is a component of thephosphatidylinositol 3 kinase (PI3K)/AKT pathway. p70S6K is downstreamof PI3K, and activation occurs through phosphorylation at a number ofsites in response to numerous mitogens, hormones and growth factors.p70S6K activity is also under the control of a mTOR-containing complex(TORC1) since rapamycin acts to inhibit p70S6K activity. p70S6K isregulated by PI3K downstream targets AKT and PKCζ. Akt directlyphosphorylates and inactivates TSC2, thereby activating mTOR. Inaddition, studies with mutant alleles of p70S6K that inhibited byWortmannin but not by rapamycin suggest that the PI3K pathway canexhibit effects on p70S6K independent of the regulation of mTORactivity.

The enzyme p70S6K modulates protein synthesis by phosphorylation of theS6 ribosomal protein. S6 phosphorylation correlates with increasedtranslation of mRNAs encoding components of the translational apparatus,including ribosomal proteins and translational elongation factors whoseincreased expression is essential for cell growth and proliferation.These mRNAs contain an oligopyrimidime tract at their 5′ transcriptionalstart (termed 5′TOP), which has been shown to be essential for theirregulation at the translational level.

In addition to its involvement in translation, p70S6K activation hasalso been implicated in cell cycle control, neuronal celldifferentiation, regulation of cell motility and a cellular responsethat is important in tumor metastases, the immune response and tissuerepair. Antibodies to p70S6K abolish the mitogenic response driven entryof rat fibroblasts into S phase, indication that p70S6K function isessential for the progression from G1 to S phase in the cell cycle.Furthermore, inhibition of cell cycle proliferation at the G1 to S phaseof the cell cycle by rapamycin has been identified as a consequence ofinhibition of the production of the hyperphosphorylated, activated formof p70S6K.

A role for p70S6K in tumor cell proliferation and protection of cellsfrom apoptosis is supported based on it participation in growth factorreceptor signal transduction, overexpression and activation in tumortissues. For example, Northern and Western analyses revealed thatamplification of the PS6K gene was accompanied by correspondingincreases in mRNA and protein expression, respectively (Cancer Res.(1999) 59: 1408-11-Localization of PS6K to Chromosomal Region 17q23 andDetermination of Its Amplification in Breast Cancer).

Chromosome 17q23 is amplified in up to 20% of primary breast tumors, in87% of breast tumors containing BRCA2 mutations and in 50% of tumorscontaining BRCA1 mutations, as well as other cancer types such aspancreatic, bladder and neuroblastoma (see M. Barlund, O. Monni, J.Kononen, R. Cornelison, J. Torhorst, G. Sauter, O.-P. Kallioniemi andKallioniemi A., Cancer Res., 2000, 60:5340-5346). It has been shown that17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K,and SIGMA1B genes (Cancer Res. (2000): 60, pp. 5371-5375).

The p70S6K gene has been identified as a target of amplification andoverexpression in this region, and statistically significant associationbetween amplification and poor prognosis has been observed. Clinicalinhibition of p70S6K activation was observed in renal carcinoma patientstreated with CCI-779 (rapamycin ester), an inhibitor of the upstreamkinase mTOR. A significant linear association between diseaseprogression and inhibition of p70S6K activity was reported. In responseto energy stress, the tumor suppressor LKB1 activates AMPK whichphosphorylates the TSC1/2 complex and enables it to inactivate themTOR/p70S6K pathway. Mutations in LKB1 cause Peutz-Jeghers syndrome(PJS), where patients with PJS are 15 times more likely to developcancer than the general population. In addition, ⅓ of lungadenocarcinomas harbor inactivating LKB1 mutations. P70S6K has beenimplicated in metabolic diseases and disorders. It was reported that theabsence of p70S6K protects against age- and diet-induced obesity whileenhancing insulin sensitivity. A role for p70S6K in metabolic diseasesand disorders such as obesity, diabetes, metabolic syndrome, insulinresistance, hyperglycemia, hyperaminoacidemia, and hyperlipidmia issupported based upon the findings.

Compounds described as suitable for p70S6K inhibition are disclosed inWO 03/064397, WO 04/092154, WO 05/054237, WO 05/056014, WO 05/033086, WO05/117909, WO 05/039506, WO 06/120573, WO 06/136821, WO 06/071819, WO06/131835, WO 08/140947, WO 10/056563, WO 10/093419, WO 12/013282, WO12/016001 and WO 12/069146.

DESCRIPTION OF THE INVENTION

It is the object of the present invention to provide novel compoundsthat modulate kinase activity. This protein kinase modulation includes,but is not limited to, p70S6K inhibition and Akt inhibition useful inthe treatment of hyperproliferative diseases, especially those relatedto the hyperactivity of the above mentioned protein kinases, such ascancer in mammals, with superior pharmacological properties both withrespect to their activities as well as their solubility, metabolicclearance and bioavailability characteristics.

As a result, this invention provides novel, heterocyclic pyrimidinyl andpyridinyl amine compounds and pharmaceutically acceptable salts,solvates or prodrugs thereof, that are kinase inhibitors and useful inthe treatment of the above mentioned diseases.

The compounds are defined by Formula (I):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

-   R¹ is Hal, LA, OH, O(LA), NH₂ and/or NH(LA), N(LA)₂, NO₂, CN, OCN,    SCN, COOH, COO(LA), CONH₂, CONH(LA), CON(LA)₂, NHCO(LA), NHCONH(LA),    NHCONH₂, NHSO₂(LA), CHO, CO(LA), SO₂NH₂, SO₂(LA), or a mono- or    bicyclic, aliphatic or aromatic homo- or heterocycle having 0, 1, 2,    3 or 4 N, S and/or O atoms and 4, 5 or 6, 7, 8, 9, or 10 skeleton    atoms which may be unsubstituted or, independently of one another,    mono-, di- or trisubstituted by Hal, LA, OH, O(LA), NH₂ and/or    NH(LA), N(LA)₂, NO₂, CN, OCN, SCN, COOH, COO(LA), CONH₂, CONH(LA),    CON(LA)₂, NHCO(LA), NHCONH(LA), NHCONH₂, NHSO₂(LA), CHO, CO(LA),    SO₂NH₂, SO₂(LA) and/or SO₂Hal or an unbranched or branched linear or    cyclic alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one    or two CH₂ groups may be replaced by an O atom and/or by an —NH—,    NH(LA), —CO—, —NHCO— or —CH═CH— group, and/or in which a CH group    may be replaced by —N—;-   R² is H, NH₂, NH(LA), N(LA)₂ or NHCO(LA);-   R³ is N or CH;-   R⁴ is H, an unbranched or branched linear or mono- or bicyclic alkyl    group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or    two CH₂ groups may be replaced by an —O—, —NH—, group, and/or in    which one or two CH groups may be replaced by —N—,    -   and/or in which 1, 2 or 3 H atoms may be replaced by Hal or OH,-   R⁵ is a monocyclic aromatic or aliphatic homo- or heterocycle having    0, 1 or 2 N, S and/or O atoms and 5 or 6 skeleton atoms which may be    unsubstituted or, independently of one another, mono-, di- or    trisubstituted by Hal, LA, OH, O(LA), NH₂ and/or NH(LA), N(LA)₂,    NO₂, CN, OCN, SCN, COOH, COO(LA), CONH₂, CONH(LA), CON(LA)₂,    NHCO(LA), NHCONH(LA), NHCONH₂, NHSO₂(LA), CHO, CO(LA), SO₂NH₂,    SO₂(LA);-   Hal is F, Cl, Br or I, and-   LA is an unbranched or branched, saturated or partially unsaturated,    linear hydrocarbon chain having 1, 2, 3 or 4 C atoms, wherein 1, 2    or 3 H atoms may be replaced by Hal.

In a preferred embodiment the compounds of the invention conform toFormula (II) in which all substituents have the meanings indicated forFormula (I):

In a further preferred embodiment the compounds of the invention conformto Subformulae 1 to 19 of Formulae (I) or (II), wherein:

-   in Subformula 1-   R¹ is Hal, LA, O(LA), CN, CONH₂, or a monocyclic aliphatic or    aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or    6 skeleton atoms,-   in Subformula 2-   R² is NH₂,-   in Subformula 3-   R³ is N,-   in Subformula 4-   R⁴ is unbranched or branched, linear or monocyclic alkyl having 1,    2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH₂ groups may    be replaced by by —O— or —NH—, and/or in which one or two CH groups    may be replaced by —N—,-   in Subformula 5-   R⁵ is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono-    or disubstituted by Hal or LA,-   in Subformula 6-   R¹ is Hal, LA, O(LA), CN, CONH₂, or a monocyclic aliphatic or    aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or    6 skeleton atoms,-   R² is NH₂,-   R³ is N,-   in Subformula 7-   R² is NH₂,-   R³ is N,-   R⁴ is unbranched or branched, linear or monocyclic alkyl having 1,    2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH₂ groups may    be replaced by an —O—, —NH—, group, and/or in which one or two CH    groups may be replaced by —N—,-   in Subformula 8-   R² is NH₂,-   R³ is N,-   R⁵ is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono-    or disubstituted by Hal or LA,-   in Subformula 9-   R¹ is Hal, LA, O(LA), CN, CONH₂, or a monocyclic aliphatic or    aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or    6 skeleton atoms,-   R² is NH₂,-   R³ is N,-   R⁵ is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono-    or disubstituted by Hal or LA,-   in Subformula 10-   R¹ is Hal, LA, O(LA), CN, CONH₂, or a monocyclic aliphatic or    aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or    6 skeleton atoms,-   R² is NH₂,-   R³ is N,-   R⁴ is unbranched or branched, linear or monocyclic alkyl having 1,    2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH₂ groups may    be replaced by an by —O— or —NH—, and/or in which one or two CH    groups may be replaced by —N—,-   in Subformula 11-   R² is NH₂,-   R³ is N,-   R⁴ is unbranched or branched, linear or monocyclic alkyl having 1,    2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH₂ groups may    be replaced by by —O— or —NH—, and/or in which one or two CH groups    may be replaced by —N—,-   R⁵ is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono-    or disubstituted by Hal or LA,-   in Subformula 12-   R¹ is Hal, LA, O(LA), CN, CONH₂, or a monocyclic aliphatic or    aromatic homo- or heterocycle having 0, 1 or 2 N or O atoms and 5 or    6 skeleton atoms,-   R² is NH₂,-   R³ is N,-   R⁴ is unbranched or branched, linear or monocyclic alkyl having 1,    2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH₂ groups may    be replaced by —O— or —NH—, and/or in which one or two CH groups may    be replaced by —N—,-   R⁵ is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono-    or disubstituted by Hal or LA,-   in Subformula 13-   R¹ is Cl, CN, CONH₂, isopropyl, isopropyloxy, ethyl, ethenyl,    ethyloxy,-   R² is NH₂,-   R³ is N,-   in Subformula 14-   R² is NH₂,-   R³ is N,-   R⁴ is branched monocyclic alkyl having 5, 6 or 7 C atoms, of which 3    or 4 C atoms are ring atoms, and in which one CH₂ group may be    replaced by —O— or —NH—, and/or in which one CH group may be    replaced by —N—,    -   or unbranched or branched linear alkyl having 5, 6 or 7 C atoms,        in which one CH₂ group may be replaced by —O— or —NH—, and/or in        which one CH group may be replaced by —N—,-   in Subformula 15-   R² is NH₂,-   R³ is N,-   R⁵ is phenyl or pyridyl, which is para-substituted by Hal and/or    meta-substituted by Hal or LA,-   in Subformula 16-   R¹ is Cl, CN, CONH₂, isopropyl, isopropyloxy, ethyl, ethenyl,    ethyloxy,-   R² is NH₂,-   R³ is N,-   R⁴ is branched monocyclic alkyl having 5, 6 or 7 C atoms, of which 3    or 4 C atoms are ring atoms, and in which one CH₂ group may be    replaced by —O— or —NH—, and/or in which one CH group may be    replaced by —N—,    -   or unbranched or branched linear alkyl having 5, 6 or 7 C atoms,        in which one CH₂ group may be replaced by —O— or —NH—, and/or in        which one CH group may be replaced by —N—,-   in Subformula 17-   R¹ is Cl, CN, CONH₂, isopropyl, isopropyloxy, ethyl, ethenyl,    ethyloxy,-   R² is NH₂,-   R³ is N,-   R⁵ is phenyl or pyridyl, which is para-substituted by Hal and/or    meta-substituted by Hal or LA,-   in Subformula 18-   R² is NH₂,-   R³ is N,-   R⁴ is branched monocyclic alkyl having 5, 6 or 7 C atoms, of which 3    or 4 C atoms are ring atoms, and in which one CH₂ group may be    replaced by —O— or —NH—, and/or in which one CH group may be    replaced by —N—,    -   or unbranched or branched linear alkyl having 5, 6 or 7 C atoms,        in which one CH₂ group may be replaced by —O— or —NH—, and/or in        which one CH group may be replaced by —N—,-   R⁵ is phenyl or pyridyl, which is para-substituted by Hal and/or    meta-substituted by Hal or LA,-   in Subformula 19-   R¹ is Cl, CN, CONH₂, isopropyl, isopropyloxy, ethyl, ethenyl,    ethyloxy,-   R² is NH₂,-   R³ is N,-   R⁴ is branched monocyclic alkyl having 5, 6 or 7 C atoms, of which 3    or 4 C atoms are ring atoms, and in which one CH₂ group may be    replaced by —O— or —NH—, and/or in which one CH group may be    replaced by —N—,    -   or unbranched or branched linear alkyl having 5, 6 or 7 C atoms,        in which one CH₂ group may be replaced by —O— or —NH—, and/or in        which one CH group may be replaced by —N—,-   R⁵ is phenyl or pyridyl, which is para-substituted by Hal and/or    meta-substituted by Hal or LA,    and pharmaceutically acceptable salts, solvates, solvates of salts,    or prodrugs thereof.

In even more preferred embodiments, the substituents designated R¹, R⁴and R⁵ in Formula (I), above, are defined as follows [with theunmodified substituents of Formula (I) remaining as defined above]:

-   R1 is formamide; ethyl; isopropyl, Hal; ethoxy, isopropoxy, vinyl;    carbonitrile; 1H-pyrazol-4-yl; 2,2,2-trifluoroethoxy;    4-fluorophenyl; 4-methoxyphenyl; 5-isoxazol-4-yl; methoxy;    1H-pyrrol-3-yl; 5-isoxazol-4-yl; cyclobutyl; cyclopropyl;    5-cyclopent-1-enyl; isopropenyl; hydroxymethyl, 3,4-difluorophenyl;    3-fluorophenyl; 2-fluorophenyl; pyridin-4-yl; 6-aminopyridin-3-yl;    2-methyl-thiazol-5-yl; 6-methylpyridin-3-yl; pyridin-3-yl;    4-hydroxymethylphenyl; (E)-2-ethoxy-vinyl and methyl;-   R4 is 2-azetidin-1-yl-ethyl; 2-dimethylaminoethyl;    2-methylaminoethyl; 2-ethylaminoethyl; 2-isopropylaminoethyl;    2-cyclopropylmethylaminoethyl; 2-methoxyethylaminoethyl;    2-cyclopropylaminoethyl; 2-aminoethyl; 2-cyclopentylaminoethyl;    1-piperidin-4-yl; 1-pyrrolidin-3-yl; 1-azetidin-3-ylmethyl;    1-methyl-azetidin-3-ylmethyl; 2-pyrrolidin-1-yl-ethyl;    2-tert-butylaminoethyl; 2-cyclopropylaminoethyl;    2-ethylisopropylaminoethyl; 2-diethylaminoethyl;    2-isobutylaminoethyl; 2-(1,1-dimethylpropylamino)-ethyl;    2-(isopropylmethylamino)-ethyl; 1-pyrrolidin-2-ylmethyl;    1-azetidin-2-ylmethyl; azetidin-3-yl;    2-(2-dimethylaminoethyl-methylamino)ethyl;    2-(2-methoxyethyl-methylamino)-ethyl; 2-piperidin-1-yl-ethyl;    2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-ethyl;    2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-ethyl;    2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethyl;    2-(3-fluoroazetidin-1-yl)-ethyl; 2-(3,3-difluoroazetidin-1-yl and    2-(3-methylazetidin-1-yl)-ethyl;-   R5 is 4-fluoro-3-trifluoromethylphenyl; 4-fluoro-3-methylphenyl;    2-trifluoromethylpyridin-4-yl; 2-isopropylpyridin-4-yl;    3-chloro-4-fluorophenyl; cyclohexyl; 3-trifluoromethylphenyl;    3-chloro-4-methoxyphenyl; 3-chloro-4-methylphenyl;    3-fluoro-4-methoxyphenyl; 3-fluoro-4-methylphenyl;    2-tert-butylpyridin-4-yl; 2-cyclopropylpyridin-4-yl;    2-ethylpyridin-4-yl; 4-methyl-3-trifluoromethylphenyl;    3-difluoromethoxy-4-fluorophenyl; 1H-pyrazol-4-yl; isoxazol-4-yl;    4-difluoromethoxyphenyl; phenyl; thiophen-3-yl; furan-3-yl;    6-chloro-pyridin-2-yl; 2-fluoropyridin-4-yl;    6-trifluoromethylpyridin-2-yl; 3-chloroophenyl; 3-fluorophenyl;    4-fluoro-3-methoxyphenyl; 3,4-difluorophenyl; 4-fluorophenyl;    4-chlorophenyl; 2-fluorophenyl; 5-chloro-6-fluoropyridin-3-yl;    2-methylpyridin-4-yl and 3-trifluoromethoxyphenyl.

In other preferred embodiments the substituents designated R¹, inFormula (I), are set out in Table 1.

TABLE 1 Preferred substituents for R¹ in Formula (I):

In other preferred embodiments the substituents designated R⁴, inFormula (I), are set out in Table 2.

TABLE 2 Preferred substituents for R⁴ in Formula (I):

In other preferred embodiments the substituents designated R5, inFormula (I), are set out in Table 3.

TABLE 3 Preferred substituents for R⁵ in Formula (I):

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another.

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into abiologically active compound according to the present invention underphysiological conditions in the living body, e.g., by oxidation,reduction, hydrolysis or the like, each of which is carried outenzymatically, or without enzyme involvement. Examples of prodrugs arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated, or wherein a sulfhydryl group forms a disulfide bridge with acarrier molecule, e.g. a peptide, that delivers the drug selectively toa target and/or to the cytosol of a cell. These compounds can beproduced from compounds of the present invention according to well-knownmethods. Other examples of prodrugs are compounds, wherein thecarboxylate in a compound of the present invention is for exampleconverted into an alkyl-, aryl-, choline-, amino, acyloxymethylester,linolenoyl-ester.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, e.g., keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,e.g., the keto or the enol form, are claimed separately and together asmixtures in any ratio. The same applies for stereoisomers, e.g.,enantiomers, cis/trans isomers, conformers and the like. If desired,isomers can be separated by methods well known in the art, e.g. byliquid chromatography. The same applies for enantiomers, e.g., by usingchiral stationary phases. Additionally, enantiomers may be isolated byconverting them into diastereomers, i.e., coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials.

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In cases where thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of thepresent invention which contain acidic groups can be present in saltform, and can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Moreprecise examples of such salts include sodium salts, potassium salts,calcium salts, magnesium salts or salts with ammonia or organic aminessuch as, for example, ethylamine, ethanolamine, triethanolamine or aminoacids. Compounds of the present invention which contain one or morebasic groups, i.e. groups which can be protonated, can be present insalt form, and can be used according to the invention in the form oftheir addition salts with inorganic or organic acids. Examples ofsuitable acids include hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, and other acids known tothe person skilled in the art. If the compounds of the present inventionsimultaneously contain acidic and basic groups in the molecule, theinvention also includes, in addition to the salt forms mentioned, innersalts or betaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to a person skilled in the art, forexample by contacting these with an organic or inorganic acid or base ina solvent or dispersant, or by anion exchange or cation exchange withother salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

The term “substituted” preferably relates to the substitution by theabove-mentioned substituents, where a plurality of different degrees ofsubstitution are possible, unless indicated otherwise.

All physiologically acceptable salts, derivatives, solvates, solvates ofsalts, and stereoisomers of these compounds, including mixtures thereofin all ratios, are also in accordance with the invention.

The compounds of Formula (I) and Formula (II) may have one or morecentres of chirality. They may accordingly occur in various enantiomericforms and be in racemic or optically active form. The inventiontherefore also relates to the optically active forms (stereoisomers),the enantiomers, the racemates, the diastereomers and hydrates andsolvates of these compounds.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3. A method for the resolution of racemates containing estergroups (for example acetyl esters) is the use of enzymes, in particularesterases.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising a compound of the present invention, or aprodrug compound thereof, or a pharmaceutically acceptable salt orsolvate thereof as an active ingredient together with a pharmaceuticallyacceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients, such as oneor more additional compounds of the present invention, or a prodrugcompound or other p70S6K inhibitors.

The pharmaceutical compositions include compositions suitable for oral,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In one embodiment, said compounds and pharmaceutical composition are forthe treatment of cancer such as brain, lung, colon, epidermoid, squamouscell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney,liver, ovarian, prostate, colorectal, uterine, rectal, oesophageal,testicular, gynecological, thyroid cancer, melanoma, hematologicmalignancies such as acute myelogenous leukemia, multiple myeloma,chronic myelogneous leukemia, myeloid cell leukemia, glioma, Kaposi'ssarcoma, or any other type of solid or liquid tumors. Preferably, thecancer to be treated is chosen from breast, colorectal, lung, prostateor pancreatic cancer or glioblastoma.

The invention also relates to the use of compounds according to theinvention for the preparation of a medicament for the treatment ofhyperproliferative diseases related to the hyperactivity of p70S6K aswell as diseases modulated by the p70S6K cascade in mammals, ordisorders mediated by aberrant proliferation, such as cancer andinflammation.

The invention also relates to a compound or pharmaceutical compositionfor treating a disease related to vasculogenesis or angiogenesis in amammal which comprises a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt, prodrugor hydrate thereof, and a pharmaceutically acceptable carrier.

In one embodiment, said compound or pharmaceutical composition is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,inflammatory bowel disease, atherosclerosis, skin diseases such aspsoriasis, eczema, and sclerodema, diabetes, diabetic retinopathy,retinopathy of prematurity and age-related macular degeneration.

This invention also relates to a compound or pharmaceutical compositionfor inhibiting abnormal cell growth in a mammal which comprises anamount of a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate or prodrug thereof, in combination with anamount of another anti-cancer therapeutic, wherein the amounts of thecompound, salt, solvate, or prodrug, and of the chemotherapeutic aretogether effective in inhibiting abnormal cell growth. Many anti-cancertherapeutics are presently known in the art. In one embodiment, theanti-cancer therapeutic is a chemotherapeutic selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.In another embodiment the anti-cancer therapeutic is an antibodyselected from the group consisting of bevacizumab, CD40-specificantibodies, chTNT-1/B, denosumab, zanolimumab, IGF1R-specificantibodies, lintuzumab, edrecolomab, WX G250, rituximab, ticilimumab,trastuzumab and cetuximab.

In yet another embodiment the anti-cancer therapeutic is an inhibitor ofanother protein kinase, auch as Akt, Axl, Aurora A, Aurora B, dyrk2,epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1, Vegfr2, Vegfr3 (also known asFlt-4), KDR, MEK, MET, Plk1, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR,Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Flt-3, PDK1 andErk.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder thatcomprises administering to the mammal an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt or solvate orprodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of a compound of the invention in this combinationtherapy can be determined as described herein. It is believed that thecompounds of the present invention can render abnormal cells moresensitive to treatment with radiation for purposes of killing and/orinhibiting the growth of such cells.

Accordingly, this invention further relates to a method for sensitizingabnormal cells in a mammal to treatment with radiation which comprisesadministering to the mammal an amount of a compound of the presentinvention or pharmaceutically acceptable salt or solvate or prodrugthereof, which amount is effective is sensitizing abnormal cells totreatment with radiation. The amount of the compound, salt, or solvatein this method can be determined according to the means for ascertainingeffective amounts of such compounds described herein. The invention alsorelates to a method for inhibiting abnormal cell growth in a mammal thatcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like. In the case of oral liquidpreparations, any of the usual pharmaceutical media may be employed,such as, for example, suspensions, elixirs and solutions; or carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. In the case of oral solid preparations the composition may takeforms such as, for example, powders, hard and soft capsules and tablets,with the solid oral preparations being preferred over the liquidpreparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed.

Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.Preferably compounds of the present invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing cancer, inflammation or other proliferativediseases for which compounds of the present invention are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.01milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose. For most large mammals, thetotal daily dosage is from about 0.2 milligrams to about 2000milligrams, preferably from about 0.5 milligram to about 1000milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 0.5 milligrams to about 1000 milligrams.These aforementioned dosage regimens may be adjusted to provide theoptimal therapeutic response.

The invention also relates to a set (kit) consisting of separate packsof

a) an effective amount of a compound according to the invention or aphysiologically acceptable salt, solvate or prodrug thereof, andb) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

Experimental Section

Some abbreviations that may appear in this application are as follows:

Abbreviations

Designation ACN acetonitrile ATP Adenosine triphosphate b Broad peak dDoublet DMSO dimethylsulfoxide DIEA N,N-Diisopropylethylamine DTTdithiothreitol EDTA Ethylenediaminetetraacetic acid equiv. equivalentsEt ethyl h hour HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHPLC High pressure liquid chromatography LC/MS Liquid chromatographycoupled to mass spectrometry m multiplet M Molecular ion m/zMass-to-charge ratio Me methyl min minute MS Mass spectrometry N Normal(unit of concentration) NMO 4-methylmorpholine N-oxide NMR NuclearMagnetic Resonance PG Protecting group psi Pounds per square inch qQuartette (or quartet) Rf Retention factor RT Room temperature Rt.Retention time s Singlet Tert Tertiary TEA Triethylamine TFATrifluoroacetic acid THAB Tetrahexylammonium bromide THF TetrahydrofuranUV ultraviolet VIS visible

The compounds of the present invention can be prepared according to theprocedures of the following Schemes and Examples, using appropriatematerials and are further exemplified by the following specificexamples.

Moreover, by utilizing the procedures described herein, in conjunctionwith ordinary skills in the art, additional compounds of the presentinvention claimed herein can be readily prepared. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable salts, such as those described above. Theamine-free bases corresponding to the isolated salts can be generated byneutralization with a suitable base, such as aqueous sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide and potassiumhydroxide, and extraction of the liberated amine-free base into anorganic solvent, followed by evaporation. The amine-free base, isolatedin this manner, can be further converted into another pharmaceuticallyacceptable salt by dissolution in an organic solvent, followed byaddition of the appropriate acid and subsequent evaporation,precipitation or crystallization.

The invention will be illustrated, but not limited, by reference to thespecific embodiments described in the following schemes and examples.Unless otherwise indicated in the schemes, the variables have the samemeaning as described above.

Unless otherwise specified, all starting materials are obtained fromcommercially suppliers and used without further purifications. Unlessotherwise specified, all temperatures are expressed in ° C. and allreactions are conducted at room temperature. Compounds were purified byeither silica chromatography or preparative HPLC.

The present invention also relates to processes for manufacturing thecompounds of Formula (I) and Formula (II) according to the hereinafterdescribed schemes and working examples.

Synthetic Schemes Describing Intermediate and End Product Compounds

Aminopyrimidine chloride intermediates were either commerciallyavailable or prepared according to the synthetic routes outlined inScheme 1, Scheme 2 and Scheme 3.

Formamidine acetate was reacted with 1a in the presence of sodiumethoxide in dry ethanol to yield 1b, which was converted to 1c by POCl3in the presence of TEA in toluene. 1c was then reacted with aqueousammonia in n-butanol at 100° C. to afford 1d.

4-amino-6-chloropyrimidin-5-ol 2a was reacted with alkylated regents toprovide the desired aminopyrimidine chloride intermediates 2b.

4,5,6-trichloropyrimidine 3a was reacted with aqueous methylamine in2-propanol to afford 5,6-dichloro-N-methylpyrimidin-4-amine 3b.

4-Imidazol-2-yl-piperidine intermediates were prepared according to thesynthestic routes outlined in Scheme 4, Scheme 5 and Scheme 6.

tert-butyl 4-formylpiperidine-1-carboxylate 4a was reacted with aqueousglyoxal in the presence of aqueous ammonium hydroxide in methanol togive tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate 4b, whichwas bromined to afford tert-butyl4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate 4c. 4c wasalkylated with 2-(2-bromoethoxy)tetrahydro-2H-pyran, followed by removalof THP group under acidic condition to yield tert-butyl4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate4d. Suzuki coupling was performed with bromide intermediate 4d to afford4e. 4e was reacted with methanesulfonyl chloride or4-methylbenzenesulfonyl chloride, followed by quenching with amineafforded 4f, which was treated with hydrogen chloride in methanol ortrifloruoacetic acid in DCM to provide the amine intermediates 4g.

tert-butyl4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate4d was converted to tert-butyl4-(1-(2-(azetidin-1-yl)ethyl)-4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate5a. Suzuki coupling was performed with bromide intermediate 5a, followedby de-Boc under acidic condition to afford4-(4-Ar-1-(2-(azetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine 5b.

Bromine ketone 6a was reacted with 1,3,5,7-tetraazaadamantane to give6b, which was underwent amide coupling to generate 6c. 6c was cyclizedin the presence of ammonium acetate to form 6d, which was then convertedto Cbz protected 6e. 6e was alkylated by 2-(bromomethyl)-1,3-dioxolanein the presence of strong base to generate 6f, followed by acidichydrolysis to yield aldehyde 6g. Reductive amination of 6g with thecorresponding secondary amines gave 6h. Deprotection of 6h to afford the4-imidazol-2-yl-piperidine intermediates 6i.

Compounds with structures as Formula (II) are prepared by the followingsynthetic routes (Scheme 7, Scheme 8 and Scheme 9).

The aminopyrimidine chlorides 7a (commercially available or preparedaccording to Scheme 1, Scheme 2 and Scheme 3) were reacted withsecondary amine 7b (prepared according to Scheme 4, Scheme 5 and Scheme6) in the presence of base to provide compounds 7c. A Suzuki couplingwas then performed with compounds 7c while R1 is bromide and boronicacid or ester to yield compounds 7d. Hydrolysis of the compounds 7cwhile R1 is nitrile provides compounds 7e.

In some embodiments of the present invention the aminopyrimidinechlorides 7a may be more generically represented as:

wherein “LG” is any leaving group typically used in nucleophilicsubstitutions, more preferably HAL, such as Cl or Br.

The aminopyrimidine chlorides 7a (commercially available or preparedaccording to Scheme 1, Scheme 2 and Scheme 3) were reacted with amines8a (prepared by de-boc of the intermediates 4e (Scheme 4)) in thepresence of base to provide compounds 8b. A mesylation reaction wasperformed on compounds 8b to form compounds 8c which was concentratedthen alkylated by the desired amine to give compounds 8d. Hydrolysis ofthe compounds 8d while R1 is nitrile provides compounds 8e.

Intermediates 6e were treated with NaH and then coupled with alkylreagents 9a, to generate 9b. Cbz group of 9b was removed by catalytichydrogenation to give 9c. Ainopyrmidine chlorides 7a were coupled with9c to afford 9d, Deprotection of Boc of 9d to produce 9e.

Analytical Methodology Analytical LC/MS was Performed Using theFollowing Three Methods: Method A:

A Discovery C¹⁸, 5 μm, 3×30 mm column was used at a flow rate of 400μL/min, sample loop 5 μL, mobile phase: (A) water with 0.1% formic acid,mobile phase, (B) methanol with 0.1% formic acid; retention times aregiven in minutes. Method details: (I) runs on a Quaternary Pump G1311A(Agilent) with UV/VIS diode array detector G1315B (Agilent) and FinniganLCQ Duo MS detector in ESI+modus with UV-detection at 254 and 280 nmwith a gradient of 15-95% (B) in a 3.2 min linear gradient (II) hold for1.4 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min lineargradient (IV) hold for 2.3 min at 15% (B).

Method B:

A Waters Symmetry C¹⁸, 3.5 μm, 4.6×75 mm column at a flow rate of 1mL/min, sample loop 10 μL, mobile phase (A) is water with 0.05% TFA,mobile phase (B) is ACN with 0.05% TFA; retention times are given inminutes. Methods details: (I) runs on a Binary Pump G1312A (Agilent)with UV/Vis diode array detector G1315B (Agilent) and Agilent G1956B(SL) MS detector in ESI+mode with UV-detection at 254 and 280 nm with agradient of 20-85% (B) in a 10 min linear gradient (II) hold for 1 minat 85% (B) (III) decrease from 20-85% (B) in a 0.2 min linear gradient(IV) hold for 3.8 min at 20% (B).

Method C:

Gradient: 4.2 min/Flow: 2 ml/min 99:01-0:100 Water+0.1%(Vol.) TFA;Acetonitril+0.1%(Vol.) TFA; 0.0 to 0.2 min: 99:01; 0.2 to 3.8 min:99:01→0:100; 3.8 to 4.2 min: 0:100; Column: Chromolith PerformanceRP18e; 100 mm long, 3 mm diameter; Wavelength: 220 nm.

Analytical Chiral HPLC

Analytical chiral HPLC was performed using a ChiralPak AD-H column(250×4.6 mm) from Daicel Chemical Industries, Ltd. on an Agilent 1100Series system. The method used a 5.0 μL injection volume, with a flowrate of 1 mL/min of 100% methanol for 15 min at 25° C., and UV-detectionat 254 and 280 nm.

Preparative HPLC

Preparative HPLC was performed using either a Waters Atlantis dC₁₈ OBD™10 μM (30×250 mm) column or a Waters Sunfire Prep C₁₈ OBD 10 μM (30×250mm) column. The columns were used at a flow rate of 60 mL/min on aWaters Prep LC 4000 System equipped with a sample loop (10 mL) and anISCO UA-6 UV/Vis detector. The mobile phase was drawn from two solventreservoirs containing (A) water and (B) HPLC-grade acetonitrile. Atypical preparative run used a linear gradient (e.g., 0-60% solvent Bover 60 min).

EXAMPLES

The working examples presented below are intended to illustrateparticular embodiments of the invention, and are not intended to limitthe scope of the specification or the claims in any way.

Preparation of the Intermediates Representative Synthesis ofIntermediate A (Scheme 1)

6-Chloro-5-ethylpyrimidin-4-amine Step 1: 5-Ethylpyrimidine-4,6-diol

To a stirred solution of sodium ethoxide (21% in ethanol, 349 mL, 1.06mol) in dry ethanol (500 mL) was added formamidine acetate (30.4 g, 0.29mol) in lots at 0° C. under nitrogen. The reaction mixture was stirredat this temperature for 15 min and then added a solution ofdiethyl-ethylmalonate (50.0 g, 0.26 mol) in ethanol (200 mL) in drops at0° C. under nitrogen. The reaction mixture was stirred at RT for 14 h.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The crude residue was dissolved in water (250mL) and acidified (pH˜3 to 4) with aqueous solution HCl (1.5 N, 100 mL).The resulting solid was filtered off, washed with water (100 mL) anddried under vacuum to afford the titled compound (27.0 g, 72.5%) aswhite solid. LCMS: Mass found (M+, 141.0), ¹H NMR (400 MHz, DMSO-d6)11.54 (bs, 2H), 7.86 (s, 1H), 2.28-2.22 (m, 2H), 0.95-0.91 (m, 3H).

Step 2: 4,6-Dichloro-5-ethylpyrimidine

To a suspension of 5-ethylpyrimidine-4,6-diol (20.0 g, 0.14 mol) in drytoluene (200 mL) was added triethylamine (20.0 mL, 0.004 mol) at RTunder nitrogen. The reaction mixture was heated to 115° C. and thenPOCl₃ (52.3 mL, 0.57 mol) was added in drops. The reaction mixture wasstirred at same temperature for 3 h. After completion of the reaction,the reaction mixture was cooled to 0° C. and quenched with ice coldwater (50 mL). The organic layer was separated, washed with saturatedsodium bicarbonate (100 mL) and dried over sodium sulphate. The organiclayer was concentrated under vacuum to afford the titled compound (22.5g, 89%) as yellow liquid. ¹H NMR (400 MHz, CDCl₃) 8.61 (bs, 1H),2.95-2.89 (m, 2H), 1.25-1.22 (m, 3H).

Step 3: 6-Chloro-5-ethylpyrimidin-4-amine

To a mixture of 4,6-Dichloro-5-ethylpyrimidine (22.5 g, 0.12 mol) in1-butanol (70 mL) in a 1 L glass pressure tube was added aqueous ammonia(26%, 150 mL) at RT. The vessel was sealed and heated to 100° C. for 12h. The reaction mixture was cooled to RT, the resulted solid wasfiltered, washed with water (50 mL) and dried under vacuum to afford thetitled compound (11.0 g, 55%) as white solid. LCMS: Mass found (M+,158.0). 1H NMR (400 MHz, CDCl3) 8.02 (s, 1H), 7.10 (bs, 2H), 2.57-2.50(m, 2H), 1.03-0.99 (m, 3H).

Representative Synthesis of Intermediate B (Scheme 2)

6-chloro-5-ethoxypyrimidin-4-amine

A reaction mixture of 4-amino-6-chloro-pyrimidin-5-ol (1000.0 mg; 6.8mmol; 1.0 eq.), cesium carbonate (2686.3 mg; 8.24 mmol; 1.2 eq.), andiodoethane (1285.9 mg; 8.24 mmol; 1.2 eq.) in acetone (10 ml) wasstirred at 50° C. overnight. The reaction solution was diluted withethyl acetate (50 ml), washed with water, then brine, dried andconcentrated. The residue was treated with ether, stirred for 30 min,filtered, collected white off solid as title compound (1165 mg in yield98%).

Intermediate C: 5,6-dichloro-N-methylpyrimidin-4-amine (scheme 3)

To a stirred suspending solution of 4,5,6-trichloro-pyrimidine (300.00mg; 1.00 eq.) in isoprpanol (1 ml), added 40% methylamine aq 1.0 ml andstirred at RT for 1 hr. The title compound was collected by filtrationand washed with water (175 mg, yield 60%)

Representative Synthesis of Intermediate D (Scheme 4)

2-[4-(4-Fluoro-3-methylphenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl-dimethylamineStep 1: tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate

A solution of tert-butyl 4-formylpiperidine-1-carboxylate (99.0 g,464.20 mmol) methanol (200 mL) was treated with 30% aqueous ammoniumhydroxide (500 mL, 3.85 mol), followed by 40% aqueous glyoxal (53.50 mL,466.42 mmol). The contents were allowed to stir at room temp for 1 hbefore it rotary evaporated to remove methanol. The remains were treatedwith brine (500 mL) and extracted with dichloromethane (1500 mL). Theorganics were dried over sodium sulfate and concentrated to a yellowoil. The oil was seeded with authentic material to afford an off-whitesolid as the title compound that was dried under vacuum for 6 h (110.37g, 439.16 mmol, 95%).

Step 2: tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate

A solution of tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate(20.04 g, 79.74 mmol) in THF (450 mL) was cooled to −46 C (bath) beforethe flask was charged with NBS (14.27 g) in equal portions (10-minapart). LCMS data indicated complete reaction after 15 min, so thecontents were concentrated to a yellow, solid foam that was furtherdried under vacuum overnight. The crude material(monobromide:dibromide=40:27) was purified by chromatography to givepure white solid (8.08 g, 24.47 mmol, 31%) as the title compound.

Step 3: tert-butyl4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

A suspension of tert-butyl4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (36.0 g, 109.02mmol) in dry DMSO (400 mL) was treated with KOH (36.0 g, 641.60 mmol,4.5 eq), and the contents became a clear-yellow solution after 20-30min. After 90 min, the solution was treated with2-(2-bromoethoxy)terahydropyran (36.0 g, 172.18 mmol, 1.2 eq). Thereaction was deemed complete after 4 h by LCMS data, so the contentswere diluted with ethyl acetate (800 mL) and washed with brine (3×800mL). The organics were dried over sodium sulfate and concentrated to anoil with an approximate 8:1 ratio of regioisomers and that major isomeris the desired one. The oil was redissolved in methanol (400 mL) andtreated with p-toluenesulfonic acid monohydrate (32.11 g, 168.80 mmol,1.5 eq). The contents were stirred at room temp for 20 min, poured intoethyl acetate (500 mL) and washed with aqueous potassium carbonate (400mL), followed by brine (2×400 mL). The organics were dried over sodiumsulfate and concentrated to a colorless oil that was further dried undervacuum for 60 min. The resultant, thick oil was suspended in diethylether (200 mL) and rolled in an ice-water-salt bath for 90 min. A whitesolid precipitated, which was filtered and dried under vacuum for 30 minto give the title compound (25.15 g, 67.20 mmol, 62%, >96% by NMR andLCMS data).

Step 4:4-[4-(4-Fluoro-3-methylphenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-[4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (1600.00 mg; 4.27 mmol; 1.00 eq.),3-fluoro-4-methyl phenyl boronic acid (855.55 mg; 5.56 mmol; 1.30 eq.),palladium bis(tributylphosphine) (436.95 mg; 0.85 mmol; 0.20 eq.) andCesium carbonate (4178.60 mg; 12.82 mmol; 3.00 eq.) in 1,4-Dioxane (10.0mL) and water (1.50 mL) in the sealed vial was stirred at 70° C. for 5hours. The crude was purified through flash chromtagraphy (EtOAc inHexanes 30% to 80%) to provide the title compound (1.2 g, 70%).

Step 5:2-[4-(4-Fluoro-3-methylphenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl-dimethylamine

To a solution of4-[4-(4-fluoro-3-methylphenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (1500.00 mg; 3.72 mmol; 1.00 eq.) in DCM (15 mL)at −78° C., were added 4-methylbenzenesulfonyl chloride (850.50 mg; 4.46mmol; 1.20 eq.) and TEA (1128.54 mg; 11.15 mmol; 3.00 eq.). The mixturewas stirred at −78° C. for 1 hour and was allowed to warm to roomtemperature and stirred overnight. DCM was removed and the residue wasdissolved in Ether. The ether solution was washed with water twice,dried over MgSO4 and concentrated. The crude product was used for thenext reaction without purification.

The mixture of above intermediate and dimethylamine (3352.05 mg; 74.35mmol; 20.00 eq, 2.0M in THF) in the sealed vial was stirred for severalhours. LC/MS and HPLC was used to monitor the reaction progress. Afterreaction was complete, the solvent was removed. The mixture was stirredfor 20 minutes with TFA to remove the Boc group. The tittle compound wasobtained through prep HPLC purification.

Representative Synthesis of Intermediate E (Scheme 5)

4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidineStep 1: tert-butyl4-(1-(2-(azetidin-1-yl)ethyl)-4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate

A solution of tert-butyl4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(22.0 g) and Et₃N (24.5 ml) in DCM (250 ml) and cool to 0° C. Mesylchloride (6.8 ml) was added dropwisely and the resulting mixture wasstirred for 1 h. The reaction was quenched with saturated aqueous NaHCO₃and extracted with DCM. The organic layer was concentrated to givetert-butyl4-(4-bromo-1-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(28.0 g).

A reaction mixture of tert-butyl4-(4-bromo-1-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(28.0 g) and azetidine (11 ml) in to DMF (200 ml) was stirred at 50° C.overnight. The reaction was diluted with EA, washed with water followedby saturated aqueous sodium chloride, dried and concentrated. Theresidue was purified by column chromatography to give tert-butyl4-(1-(2-(azetidin-1-yl)ethyl)-4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylateas off-white solid. (17.2 g).

Step 2:4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidine

A mixture of4-[1-(2-Azetidin-1-yl-ethyl)-4-bromo-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (8800.00 mg; 21.29 mmol; 1.00 eq.),4-fluoro-3-methylphenylboronic acid (3932.91 mg; 25.55 mmol; 1.20 eq.)and Cs2CO3 (13872.97 mg; 42.58 mmol; 2.00 eq.) in dioxane (80 ml) andwater (8 ml) was purged by argon for 10 min, thenBis(tri-t-butylphosphine)palladium(0) (435.20 mg; 0.85 mmol; 0.04 eq.)was added under argon flow and purged by argon for 1 min. The resultingmixture was stirred at 50 C overnight. The reaction solution was dilutedwith ethyl acetate 250 ml, washed with brine 100 ml×2. The organic layerwas dried and concentrated to afford the crude product which is purifiedby biotage Ki-Sil column to yield4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (9370.00 mg; 99% yield).

To a solution of4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester in 55 ml of methanol, 4.0M HCl in dioxane (52.87ml; 211.49 mmol; 10.00 eq.) was added slowly. the reaction mixture wasstirred at RT for 4 hrs. LCMS showed the reaction was done. Off-whiteprecipitate formed after 1 h stirring. The solid was collected byfiltration and washed with ether 3 times to yield a white solid (8.78 g)as the pure title compound. The mother liquid was concentrated todryness and added ether (30 mL) and 5 ml of methanol. The solid wascollected by filtration and washed with ether 3 time to provide another0.82 g of the title compound as off-white solid (total yield: 100%)

Representative Synthesis of Intermediate F (Scheme 6)4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine

Step 1: 2-amino-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanonehydrochloride

2-Bromo-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone (10.00 g; 35.08mmol; 1.00 eq.) was added to a solution of1,3,5,7-tetraaza-tricyclo[3.3.1.13,7]decane (5.80 g; 41.37 mmol; 1.18eq.) in CCl4 100 ml, stirred overnight. The prepcipate was filtered and,collected as a white solid.

The above solid was added ethanol 100 ml, and then 28 ml concentrated36.5% HCl (aq) and stirred at RT over weekend, filtered off the solid.The filtrate was concentrated and solid came out. 10 ml of isopropanol(contained 1% HCl) was added, filtered and collected white solid as thetitle compound 5.22 g, 57.8%

Step 2: tert-butyl4-((2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate

To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester(9611.92 mg; 41.92 mmol; 1.08 eq.) in THF 100 ml, added4-methyl-morpholine (14.51 ml; 131.98 mmol; 3.40 eq.), The reactionmixture was cooled to −10° C., 3-methyl-butyryl chloride (5.03 ml; 38.82mmol; 1.00 eq.) was added dropwise and maintaining the temperature below−5° C. after stirring for 30 mins at from −5° C. to 10° C.,2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl-ammonium chloride(10.00 g; 38.82 mmol; 1.00 eq.) was added at −5° C. and stirred themixture for 20 mins and then RT for 1 h. Added brine, extracted with EA,washed with brine, dried and concentrated. The crude oil was treatedwith ether. The white solid was collected as the title compound (12g,yield 71.5%).

Step 3: tert-butyl4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

A mixture of4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-1-carboxylicacid tert-butyl ester (2900.00 mg; 6.71 mmol; 1.00 eq.), triethylamine(0.94 ml; 6.71 mmol; 1.00 eq.), and ammonium acetate (3618.76 mg; 46.95mmol; 7.00 eq.) in 20 ml of n-butanol was placed in microwave (150° C.)for 20 min. after cooling to rt, the reaction mixture was diluted with150 ml of ethyl acetate and washed with water, 5% NaHCO₃ aq, then brineand concentrated. The residue was treated with ether and collected whitsolid as title compound (1500 mg, 54% yield).

Step 4: benzyl4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

To4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (6.00 g; 14.51 mmol; 1.00 eq.) in 10 ml ofmethanol 4.0M HCl in dioxane 15 ml was added. The reaction mixture wasstirred at RT overnight and concentrated to yield4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidinehydrochloride salt as a white solid.

To 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidinehydrochloride salt (1510.00 mg; 3.91 mmol; 1.00 eq.) in DCM was addedEthyldiisopropylamine (2.81 ml; 15.64 mmol; 4.00 eq.) and stirred for 5mins. N-(Benzyloxycarbonyloxy) succinimide (1169.26 mg; 4.69 mmol; 1.20eq.) was then added. The reaction mixture was stirred at RT overnight.The reaction mixture was diluted with DCM, washed with water, 5% NaHCO₃aq and brine. The organic layer was dried and concentrated. The residuewas subjected to SNAP column (100 g), eluted with 20-80% EA in hexane toafford the title compound (1310 mg, yield 74.9%).

Step 5: Benzyl4-(1-((1,3-dioxolan-2-yl)methyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

The solution of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid benzyl ester (1100.00 mg; 2.46 mmol; 1.00 eq.) in 2.0 ml of THF wascooled to −20° C., NaHMDS (541.00 mg; 2.95 mmol; 1.20 eq.) was addeddropwise and the resulting mixture was stirred at RT for 30 mins.2-Bromomethyl-[1,3]dioxolane (0.76 ml; 7.38 mmol; 3.00 eq.) was addedand stirred at RT for 5 min. DMSO (10 ml) was added and the mixture wasplaced in microwave at 100° C. for 2 hr. The reaction mixture was cooledand diluted with water and extracted with EA. The organic layer waswashed with brine, separated, dried and concentrated. The residue wassubjected to snap column (100 g), eluted with 20%-80% EA in hexane togive the title compound (1000 mg, yield 76.2%).

Step 6: Benzyl4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-oxoethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

The reaction mixture of benzyl4-(1-((1,3-dioxolan-2-yl)methyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(1450.00 mg; 2.72 mmol; 1.00 eq.) and toluene-4-sulfonic acidmonohydrate (5169.79 mg; 27.18 mmol; 10.00 eq.) in 30 ml of acetone and2.5 ml of water was stirred at 50° C. for one week. LC-MS showed some amixture of the desired product, 30% of starting material and some byproducts. The reaction mixture was concentrated and added 50 ml water,extracted with EA. The combined organic layers were washed with brine,dried and concentrated. The residue was subjected to SNAP column (100g), eluted with 0-100% EA in hexane, then eluted with 10% methanol inDCM to afford the tile compound as yellow oil (480 mg, yield 36%) with arecovery of some starting material.

Step 7: Benzyl4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

3-fluoro-azetidine hydrochloride (66.99 mg; 0.45 mmol; 1.05 eq.) in 1 mlof DCE was added ethyldiisopropylamine (0.15 ml; 0.86 mmol; 2.00 eq.).After stirring at RT for 10 mins,4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-oxo-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid benzyl ester (211.00 mg; 0.43 mmol; 1.00 eq.) was added, followedby sodium triacetoxyborohydride (274.09 mg; 1.29 mmol; 3.00 eq.). Theresulting mixture was stirred overnight at RT. After workup, the titlecompound was obtained by pre-PLC purification.

Step 8:4-(4-(4-Fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine

To4-[1-[2-(3-f-azetidin-1-yl)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid benzyl ester (200.00 mg; 0.36 mmol; 1.00 eq.) in 10 ml of methanolwas added ammonium format (229.90 mg; 3.65 mmol; 10.00 eq.) and 10% Pd/C(wet) 200 mg. The mixture was stirred at RT for 1 hr. Filtered off Pd/C.The filtrate was concentrated and then dissolved in EtOAc, washed with5% NaHCO3, then brine, dried and concentrated. The crude title compound(138 mg, yield 91.3%) was directly used for the next step reactionwithout purification.

Example Compounds According to Formula (I) and Formula (II)5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“1”)

A mixture of 5-bromo-6-chloropyrimidin-4-amine (357.2 mg; 1.71 mmol;1.02 eq.),4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine(550.00 mg; 1.68 mmol; 1.0 eq.), potassium carbonate (464.4 mg; 3.36mmol; 2.0 eq.) in DMSO (6.0 ml) was stirred at 60° C. overnight. Thereaction mixture was poured into water. The precipitate was filtered,washed with water and dried under vacuum to afford the title compound in86% yield. LC-MS: (M+1=499, obsd.=499).

5-Bromo-6-{4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“2”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=499, obsd.=499).

5-Bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“3”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=467, obsd.=467).

5-Bromo-4-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine(“4”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 5-bromo-4-chloropyrimidine instead of5-bromo-6-chloropyrimidin-4-amine. LC-MS: (M+1=452, obsd.=452).

3-bromo-4-(4-{4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidin-1-yl)pyridine(“5”)

A mixture of 3-bromo-4-chloropyridine (100.0 mg; 0.52 mmol; 1.0 eq.),4-[4-(3-trifluoromethyl-phenyl)-1h-imidazol-2-yl]-piperidine (153.4 mg;0.52 mmol; 1.0 eq.), N,N-diisopropylethylamine (0.26 ml; 1.56 mmol; 3.0eq.) in NMP (2.0 ml) in a microwave vial was heated at 160° C. for 4 h.The reaction mixture was poured into water. The precipitate wasfiltered, washed with water and dried under vacuum to afford the titlecompound in 64% yield. LC-MS: (M+1=451, obsd.=451).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehyde(“6”)

A mixture of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine(600.00 mg; 1.83 mmol; 1.0 eq.),4-amino-6-chloropyrimidine-5-carbaldehyde (303.25 mg; 1.92 mmol; 1.05eq.), DIEA (0.95 ml; 5.5 mmol; 3.0 eq.) in acetonitrile (10.0 ml) washeated at 40° C. for 1 h. The reaction mixture was poured into water.The precipitate was filtered, washed with water and dried under vacuumto afford the title compound in 85% yield. LC-MS: (M+1=449, obsd.=449).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“7”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehydeusing 4-amino-6-chloropyrimidine-5-carbonitrile instead of4-amino-6-chloropyrimidine-5-carbaldehyde. LC-MS: (M+1=446, obsd.=446).

4-Amino-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“8”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=503, obsd.=503).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-methoxy-pyrimidin-4-ylamine(“9”)

A mixture of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine(40.00 mg; 0.12 mmol; 1.0 eq.), 6-chloro-5-methoxypyrimidin-4-amine(20.48 mg; 0.13 mmol; 1.05 eq.), potassium carbonate (33.78 mg; 0.24mmol; 2.0 eq.) in DMSO (1.00 ml) in a microwave vial was heated at 150°C. for 2 h. LC-MS show 40% conversion and product eluted closely to theamine starting material. The reaction mixture was workup and the crudewas purified by reverse phase pre-HPLC (Waters, acetonitrile/0.1% TFA inwater) to yield desired product in 22% yield. LC-MS: (M+1=451,obsd.=451).

5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“10”)

A mixture of5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine(100.0 mg; 0.2 mmol; 1.0 eq.), (4-fluorophenyl)boronic acid (56.0 mg;0.4 mmol; 2.0 eq.), palladium(II) acetate (2.25 mg; 0.01 mmol; 0.05eq.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (8.22 mg; 0.02mmol; 0.1 eq.) and cesium carbonate (195.7 mg; 0.6 mmol; 3.0 eq.) indioxane (4 ml) and water (0.5 ml) in the microwave vial was heated at100° C. for 30 min. The reaction mixture was workup and the crude waspurified by reverse phase chromatography (Yamazen, acetonitrile/0.1%NH4OH in water). The pure fractions were concentrated to dryness undervacuum. The white solid was dissolved in water and acetonitrile, 200 □Lof 0.5 N HCl was added. The excess of HCl was removed by concentratingunder vacuum for 20 min. The resulting solution was then lyophilized toafford the the title compound as HCl salt in 74% yield. LC-MS: (M+1=515,obsd.=515).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamine(“11”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=527, obsd.=527).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“12”)

The title compound was obtained as the de-brominating by-product duringthe preparation of6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamine.LC-MS: (M+1=421, obsd.=421).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-p-tolyl-pyrimidin-4-ylamine(“13”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-methylphenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=511, obsd.=511).

[4-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-phenyl]-methanol(“14”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-(hydroxymethyl)benzeneboronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=527, obsd.=527).

3-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-benzonitrile(“15”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 3-cyanophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=522, obsd.=522).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylamine(“16”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-10[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (4-trifluoromethyl)phenylboronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=565, obsd.=565).

4-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-benzonitrile(“17”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-cyanophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=522, obsd.=522).

2-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-benzonitrile(“18”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 2-cyanophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=522, obsd.=522).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(6-methyl-pyridin-3-yl)-pyrimidin-4-ylamine(“19”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 6-methylpyridin-3-yl)boronic acid instead of 4-fluorophenylboronicacid. LC-MS: (M+1=512, obsd.=512).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(5-methyl-thiophen-2-yl)-pyrimidin-4-ylamine(“20”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 5-methylthiophene-2-boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=517, obsd.=517).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-phenyl-pyrimidin-4-ylamine(“21”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing phenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS:(M+1=497, obsd.=497).

5-(3-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“22”)

The title compound was prepared in an analogous manner as5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=515, obsd.=515).

5-(2-Fluorophenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“23”)

The title compound was prepared in an analogous manner as5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 2-fluorophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=515, obsd.=515).

5-(2-Chlorophenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“24”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 2-chlorophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=531, obsd.=531).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(6-morpholin-4-yl-pyridin-3-yl)-pyrimidin-4-ylamine(“25”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (6-morpholinopyridin-3-yl)boronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=583, obsd.=583).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidin-4-ylamine(“26”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (6-(piperazin-1-yl)pyridin-3-yl)boronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=582, obsd.=582).

5-(6-Fluoro-pyridin-3-yl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“27”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (6-fluoropyridin-3-yl)boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=516, obsd.=516).

6′-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-[5,5′]bipyrimidinyl-2,4′-diamine(“28”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (2-aminopyrimidin-5-yl)boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=514, obsd.=514).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(3-methoxyphenyl)-pyrimidin-4-ylamine(“29”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 3-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=527, obsd.=527).

5-(3,4-Difluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“30”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 3,4-difluorophenylboronic acid instead of 4-fluorophenylboronicacid. LC-MS: (M+1=533, obsd.=533).

6′-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-N2,N2-dimethyl-[5,5′]bipyrimidinyl-2,4′-diamine(“31”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (2-(dimethylamino)pyrimidin-5-yl)boronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=542, obsd.=542).

5-(4-Aminomethyl-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“32”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (4-(aminomethyl)phenyl)boronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=526, obsd.=526).

5-(4-Methoxy-phenyl)-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“33”)

The title compound was prepared in an analogous manner as6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamineusing5-Bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineinstead of5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=495, obsd.=495).

5-(4-Methoxy-phenyl)-4-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine(“34”)

The title compound was prepared in an analogous manner as6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamineusing5-Bromo-4-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidineinstead of5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=480, obsd.=480).

3-(4-methoxyphenyl)-4-(4-{4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidin-1-yl)pyridine(“35”)

The title compound was prepared in an analogous manner as6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamineusing3-bromo-4-(4-{4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidin-1-yl)pyridineinstead of5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=479, obsd.=479).

(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-methanol(“36”)

The reaction mixture of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbaldehyde(23.00 mg; 0.05 mmol; 1.0 eq.) and sodium borohydride (7.8 mg; 0.21mmol; 4.0 eq.) in EtOH (2.00 ml) was stirred at room temperature overweekend. The reaction mixture was workup and purified by reverse phasechromatography (Yamazen, acetonitrile/0.1% NH4OH in water). The purefractions were lyophilized to afford the title compound in 65% yield.LC-MS: (M+1=451, obsd.=451).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide(“37”)

Hydrogen peroxide (0.40 ml; 4.49 mmol; 40.0 eq.) was added dropwise tothe mixture of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile(50.0 mg; 0.11 mmol; 1.0 eq.) and potassium carbonate (124.1 mg; 0.9mmol; 8.0 eq.) in DMSO (3.0 ml) at room temperature. The resultingmixture was then stirred at 40° C. for 5 hours. The reaction mixture waspoured into water, filtered and washed with water. The crude waspurified by reverse phase chromatography (Yamazen, acetonitrile/0.1%NH4OH in water). The fractions were evaporated to dryness under vacuum.The white solid was dissolved in water and acetonitrile, 200 □L of 0.5NHCl was added. The clear solution was then evaporated under vacuum for10 min to remove excess of HCl. The solution was then lyophilized toyield the title compound as HCl salt in 88% yield. LC-MS: (M+1=464,obsd.=464).

4-Amino-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“38”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=521, obsd.=521).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-4-yl-pyrimidin-4-ylamine(“39”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-pyridylboronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=498, obsd.=498).

5-(6-Amino-pyridin-3-yl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“40”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 2-aminopyridine-5-boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=513, obsd.=513).

5-Bromo-4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine(“41”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 5-bromo-4-chloropyrimidine instead of5-bromo-6-chloropyrimidin-4-amine. LC-MS: (M+1=484, obsd.=484).

5-(4-Fluoro-phenyl)-4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine(“42”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing5-bromo-4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidineinstead of5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine.LC-MS: (M+1=500, obsd.=500).

5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“43”)

The title compound was prepared in an analogous manner as5-bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=485, obsd.=485).

5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“44”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing5-bromo-4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidineinstead of5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine.LC-MS: (M+1=501, obsd.=501).

(E)-3-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-acrylicacid methyl ester (“45”)

To a mixture of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbaldehyde(100 mg; 0.22 mmol; 1.0 eq.) in DMSO (2 mL), methyl(triphenylphosphoranylidene)acetate (82.0 mg; 0.25 mmol; 1.1 eq.),lithium chloride (19.1 mg; 0.45 mmol; 2.0 eq.) and triethylamine (0.04ml; 0.27 mmol; 1.2 eq.) were added. The resulting suspension was stirredat 60° C. overnight. The crude was purified by pre-HPLC (Waters, basiccondition) to afford the title compound in 72% yield. LC-MS: (M+1=505,obsd.=505).

(E)-3-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-acrylamide(“46”)

A mixture ofE)-3-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-acrylicacid methyl ester (15.0 mg; 0.03 mmol; 1.0 eq.) in 7M ammonia in MeOH(2.1 ml; 14.8 mmol; 500 eq.) was stirred at 70° C. overnight. The crudereaction mixture was purified by reverse phase chromatography (Waters,with acetonitrile/water under basic condition). The fractions wereconcentrated to dryness and then redissolved in water and acetonitrile.200 □L of 0.5N HCl was added and the excess of HCl was removed undervacuum and then lyophilized to afford the title compound as HCl salt.LC-MS: (M+1=490, obsd.=490).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(5-methoxy-pyridin-3-yl)-pyrimidin-4-ylamine(“47”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (5-methoxypyridin-3-yl)boronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=528, obsd.=528).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-[5,5′]bipyrimidinyl-4-ylamine(“48”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing pyrimidin-5-ylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=499, obsd.=499).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(1H-indol-5-yl)-pyrimidin-4-ylamine(“49”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (1H-indol-5-yl)boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=536, obsd.=536).

5-(6-Chloro-pyridin-3-yl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“50”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (1H-indol-5-yl)boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=532, obsd.=532).

5-(3-Chloro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“51”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 3-chlorophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=531, obsd.=531).

4-(4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-2-fluoro-benzonitrile(“52”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-15[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-cyano-3-fluorophenylboronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=540, obsd.=540).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-3-yl-pyrimidin-4-ylamine(“53”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 4-cyano-3-fluorophenylboronic acid instead of4-fluorophenylboronic acid. LC-MS: (M+1=498, obsd.=498).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-((E)-3-methoxy-propenyl)-pyrimidin-4-ylamine(“54”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (E)-2-(3-methoxypropen-1-yl)boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=491, obsd.=491).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(2-methyl-thiazol-5-yl)-pyrimidin-4-ylamine(“55”)

The title compound was prepared in an analogous manner as5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing (2-methylthiazol-5-yl)boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=518, obsd.=518).

5-Bromo-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“56”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=582, obsd.=582).

5-(4-Fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“57”)

The title compound was prepared in an analogous manner as5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing5-Bromo-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineinstead of5-bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine.LC-MS: (M+1=612, obsd.=612).

5-(2-Fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-yl}-pyrimidin-4-ylamine(“58”)

The title compound was prepared in an analogous manner as5-(4-Fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 2-fluorophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=598, obsd.=598).

5-(3,4-Difluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“59”)

The title compound was prepared in an analogous manner as6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamineusing 3,4-difluorophenylboronic acid instead of 4-fluorophenylboronicacid. LC-MS: (M+1=616, obsd.=616).

6-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-vinyl-pyrimidin-4-ylamine(“60”)

The title compound was prepared in an analogous manner as6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamineusing vinylboronic acid pinacol ester instead of 4-fluorophenylboronicacid. LC-MS: (M+1=530, obsd.=530).

5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“61”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing1-(2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)ethyl)piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=596, obsd.=596).

5-(4-Fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“62”)

The title compound was prepared in an analogous manner as5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing5-bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineinstead of5-bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine.LC-MS: (M+1=612, obsd.=612).

5-(2-Fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“63”)

The title compound was prepared in an analogous manner as5-(4-fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 2-fluorophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=612, obsd.=612).

5-(3-Fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“64”)

The title compound was prepared in an analogous manner as5-(4-fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid.LC-MS: (M+1=612, obsd.=612).

6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-vinyl-pyrimidin-4-ylamine(“65”)

The title compound was prepared in an analogous manner as5-(4-fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing vinylboronic acid pinacol ester instead of 4-fluorophenylboronicacid. LC-MS: (M+1=544, obsd.=544).

6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“66”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 6-chloropyrimidin-4-amine instead of5-bromo-6-chloropyrimidin-4-amine. LC-MS: (M+1=518, obsd.=518).

5-Bromo-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“67”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=556, obsd.=556).

6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“68”)

The title compound was prepared in an analogous manner as5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing5-Bromo-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineinstead of5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine.LC-MS: (M+1=572, obsd.=572).

6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-4-yl-pyrimidin-4-ylamine(“69”)

The title compound was prepared in an analogous manner as6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamineusing 4-pyridinylboronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=555, obsd.=555).

6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-4-yl-pyrimidin-4-ylamine(“70”)

The title compound was prepared in an analogous manner as6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine2-aminopyridine-5-boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=570, obsd.=570).

6′-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-[5,5′]bipyrimidinyl-2,4′-diamine(“71”)

The title compound was prepared in an analogous manner as6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine2-aminopyridine-5-boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=571, obsd.=571).

6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropenyl-pyrimidin-4-ylamine(“72”)

The title compound was prepared in an analogous manner as6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamineusing 2-Isopropenyl boronic acid pinacol ester instead of4-fluorophenylboronic acid. LC-MS: (M+1=518, obsd.=518).

6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-vinyl-pyrimidin-4-ylamine(“73”)

The title compound was prepared in an analogous manner as6-{4-[1-(2-Dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamineusing vinyboronic acid pinacol ester instead of 4-fluorophenylboronicacid. LC-MS: (M+1=504, obsd.=504).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“74”)

The title compound was prepared in an analogous manner as4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=515, obsd.=515).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“75”)

The title compound was prepared in an analogous manner as4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[1-(2-Azetidin-1-yl-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidinehydrochloride instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=481, obsd.=481).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“76”)

The title compound was prepared in an analogous manner as4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=495, obsd.=495).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“77”)

The title compound was prepared in an analogous manner as4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1h-imidazol-2-yl]-piperidinetrifluoroacetate instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=435, obsd.=435).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“78”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=533, obsd.=533).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“79”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-chloro-4-fluorophenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=499, obsd.=499).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“80”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=453, obsd.=453).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“81”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=513, obsd.=513).

6-(4-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“82”)

In a 10 mL round-bottom flask containing6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-vinyl-pyrimidin-4-ylamine;compound with trifluoro-acetic acid (25.00 mg; 0.04 mmol; 1.00 eq.) inmethanol (2.00 ml; 49.37 mmol; 1231.95 eq.) under argon was slowlypoured 10% Pd/C (80.00 mg; 0.75 mmol; 18.76 eq.). The round-bottom flaskwas vacuumed and then filled with H₂. The procedure was repeated for 4more times before the mixture was stirred at rt for O/N under H₂(balloon). The obtained mixture was filtered and then purified withWaters pre-HPLC. LC-MS: (M+1=506, obsd.=506).

5-(2-Cyclopropylethyl)-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“83”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineusing(E)-5-(2-cyclopropylvinyl)-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=546, obsd.=546).

6-(4-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2-ethoxyethyl)pyrimidin-4-amine(“84”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineusing(E)-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2-ethoxyvinyl)pyrimidin-4-amine.LC-MS: (M+1=550, obsd.=550).

(E)-5-(2-Cyclopropylvinyl)-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“85”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amineusing (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=544, obsd.=544).

(E)-6-(4-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2-ethoxyvinyl)pyrimidin-4-amine(“86”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amineusing (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=548, obsd.=548).

2-(4-(4-Amino-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol(“87”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amineusing2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=612, obsd.=612).

Methyl4-(4-amino-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)benzoate(“88”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amineusing methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=612, obsd.=612).

4-(4-Amino-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)benzoicacid (“89”)

In a round-bottom flask containing4-(4-Amino-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-benzoicacid methyl ester (25.70 mg; 0.04 mmol; 1.00 eq.) was added 1N lithiumhydroxide monohydrate (0.08 mg; 0.00 mmol; 0.05 eq.) water solutionfollowed by THF (2.00 ml; 24.69 mmol; 593.43 eq.). The mixture wasstirred at rt for 4 h before it was concentrated and purified withwaters pre-HPLC. LC-MS: (M+1=598, obsd.=598).

5-(Cyclopent-1-en-1-yl)-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“90”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amineusing 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=612, obsd.=612).LC-MS: (M+1=544, obsd.=544).

5-Cyclopropyl-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“91”)

In a microwave vial containing5-bromo-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(70.00 mg; 0.13 mmol; 1.00 eq.) in Toluene (3.50 ml) and water (0.35 ml)was added 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.09ml; 0.50 mmol; 4.00 eq.), Palladium acetate (4.24 mg; 0.02 mmol; 0.15eq.), Tricyclohexyl-phosphane (10.58 mg; 0.04 mmol; 0.30 eq.) andPotassium phosphonate (112.16 mg; 0.53 mmol; 4.20 eq.). The mixture wasstirred at 100° C. for 5 h before the reaction mixture was filtered,concentrated and purified via waters pre-HPLC. LC-MS: (M+1=518,obsd.=518).

5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“92”)

The reaction mixture of 6-chloro-5-ethyl-pyrimidin-4-ylamine (50.00 mg;0.32 mmol; 1.00 eq.),4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine(138.05 mg; 0.33 mmol; 1.05 eq.) and DIEA (65.77 mg; 0.48 mmol; 1.50eq.) in DMSO (1.5 ml) was placed in microwave at 125° C. for 1 hr. foundsmall amount desired, mostly was sm, 140° C. for another 1 hr, moreproduct formed, 150° C. for another 1 hr, purified the product by HPLC,collected title compound 33 mg, yield 16%. LC-MS (M+1=536, obsd.=536).

5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-methylazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“93”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amineusing4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-methylazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidineinstead of4-[1-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine.LC-MS: (M+1=532, obsd.=532).

6-(4-(1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“94”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amineusing4-(1-(2-(3,3-difluoroazetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidineinstead of4-[1-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine.

LC-MS: (M+1=554, obsd.=554).

6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-((ethyl(methyl)amino)methyl)pyrimidin-4-amine(“95”)

Step 1:4-amino-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbaldehyde

The reaction mixture of 4-Amino-6-chloro-pyrimidine-5-carbaldehyde(150.00 mg; 0.95 mmol; 1.00 eq.),4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate (2) (594.52 mg; 0.95 mmol; 1.00 eq.) and Triethyl-amine(0.80 ml; 5.71 mmol; 6.00 eq.) in MeCN 4 ml were stirred at RT for 2 hr,Ic-ms showed desired as major. Filtrate, collected white solid as4-amino-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbaldehyde,277 mg, yield 56.2%. LC-MS: (M+1=506, obsd.=506).

Step 2:6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-((ethyl(methyl)amino)methyl)pyrimidin-4-amine

To a solution of4-Amino-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehyde(90.00 mg; 0.18 mmol; 1.00 eq.) in 1 ml DCE added ethyl-methyl-amine(0.02 ml; 0.19 mmol; 1.05 eq.) and sodium p-triacetoxyborohydride(113.20 mg; 0.53 mmol; 3.00 eq.), stirred for overnight at RT, Ic-msshowed desired (<30%, major ms 618/619), purified by prep HPLC,collected title compound. LC-MS: (M+1=549, obsd.=549).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine(“96”)

Step 1: 6-chloro-5-isopropoxypyrimidin-4-amine

A reaction mixture of 4-Amino-6-chloro-pyrimidin-5-ol (500.00 mg; 3.44mmol; 1.00 eq.), Cs₂CO₃ (2238.59 mg; 6.87 mmol; 2.00 eq.), and2-Iodo-propane (1167.95 mg; 6.87 mmol; 2.00 eq.) in acetone 10 ml wasstirred at 65° C. for 3 hr, desired as major, also found dialkylation byproduct, removed off solvent, treated with ethyl acetate, solid cameout, filtered, washed with ether, collected product6-chloro-5-isopropoxypyrimidin-4-amine 160 mg, yield 24.8%

Step 2:6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine

A reaction mixture of 6-Chloro-5-isopropoxy-pyrimidin-4-ylamine (40.00mg; 0.21 mmol; 1.00 eq.),4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate (2) (133.13 mg; 0.21 mmol; 1.00 eq.), and Cs2CO3(277.84 mg; 0.85 mmol; 4.00 eq.) in DMSO 5.0 ml was stirred at 120° C.for 2 days, purified the product by HPLC, collected title compound 64mg, yield 45.5%. LC-MS: (M+1=548, obsd.=548).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine(“97”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amineusing 6-chloro-5-methoxypyrimidin-4-amine Instead6-chloro-5-isopropoxypyrimidin-4-amine LC-MS (M+1=520, obsd.=520).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“98”)

A mixture of6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine(100.00 mg; 0.18 mmol; 1.00 eq.),4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (77.63 mg; 0.26 mmol; 1.50 eq.), and in dioxane 2ml and water 0.15 ml was degas, added Pd(t-Bu₃)₂ 13 mg, stirred at 50°C. for overnight. Added methanol 5 ml, 4.0M HCl in dioxane 5 ml, stirredat RT for 4 hr, removed off solvent and purified by prep HPLC, collectedtitle compound 15 mg, yield 12.7%. LC-MS: (M+1=556, obsd.=556).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“99”)

Step 1:3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridineHydrochloridesalt

A mixture of4-[1-(2-Azetidin-1-yl-ethyl)-4-bromo-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (880.00 mg; 2.13 mmol; 1.00 eq.), and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-pyridine(609.67 mg; 3.19 mmol; 1.50 eq.) in dioxane 8 ml and water 0.6 ml, wasadded Cs₂CO₃ (1387.30 mg; 4.26 mmol; 2.00 eq.), purged with argon, thenadded Pd(t-Bu₃P)₂ (108.80 mg; 0.21 mmol; 0.10 eq.), stirred at 50° C.for overnight. Lc-ms showed desired as major. Purified the product byprepHPLC, collected desired 700 mg. yield 68.6 LC-MS: (M+1=380,obsd.=380).

Above product 700 mg was added methanol 3 ml, 4.0M HCl in dioxane 3 ml,stirred at RT for 4 hr. Ic-ms showed desired, filtered, collected whitesolid as title compound 650 mg, yield 58%.

Step 2:6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine

A reaction mixture of 6-Chloro-5-ethyl-pyrimidin-4-ylamine (50.00 mg;0.32 mmol; 1.00 eq.),3-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-5-trifluoromethyl-pyridinehydrochloride (3) (155.08 mg; 0.32 mmol; 1.00 eq.), and Cs₂CO₃ (206.74mg; 0.63 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2days, purified by HPLC, title compound 81 mg, 41.5%. LC-MS: (M+1=501,obsd.=501).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“100”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using4-(1-(2-(azetidin-1-yl)ethyl)-4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=516, obsd.=516).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-chloropyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“101”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-chloropyridineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=467, obsd.=467).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethoxypyrimidin-4-amine(“102”)

A reaction mixture of 6-Chloro-5-ethoxy-pyrimidin-4-ylamine (30.00 mg;0.17 mmol; 1.00 eq.),4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate (2) (107.92 mg; 0.17 mmol; 1.00 eq.), and Cs₂CO₃(225.22 mg; 0.69 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C.for overnight. Purified the product by prep HPLC, collected titlecompound 27 mg, yield 24%. LC-MS: (M+1=534, obsd.=534).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine(“103”)

Step 1:6-chloro-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine

A reaction mixture of 4-Amino-6-chloro-pyrimidin-5-ol (500.00 mg; 3.44mmol; 1.00 eq.), Cs2CO3 (1343.15 mg; 4.12 mmol; 1.20 eq.), andTrifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.59 ml;4.12 mmol; 1.20 eq.) in DMF 2 ml was stirred at RT for overnight. Ic-msshowed clean desired, worked up, purified by HPLC, collected titlecompound 610 mg, yield 78%.

Step 2:6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine

A reaction mixture of6-Chloro-5-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-ylamine (45.00 mg; 0.20mmol; 1.00 eq.),4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate (2) (123.48 mg; 0.20 mmol; 1.00 eq.), and Cs₂CO₃(257.71 mg; 0.79 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C.for 5 days. Purified by HPLC, collected title product 54 mg, yield39.8%. LC-MS: (M+1=588, obsd.=588).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-chloropyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“104”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-chloropyridineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=467, obsd.=467).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“105”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=501, obsd.=501).

5-(2-(1-(6-amino-5-ethylpyrimidin-4-yl)piperidin-4-yl)-1-(2-(azetidin-1-yl)ethyl)-1H-imidazol-4-yl)-2-fluorobenzamide(“106”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using5-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-fluorobenzamideinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=493, obsd.=493).

5-(2-(1-(6-amino-5-ethylpyrimidin-4-yl)piperidin-4-yl)-1-(2-(azetidin-1-yl)ethyl)-1H-imidazol-4-yl)-2-methoxybenzamide(“107”)

The title compound was obtained when prepared5-(2-(1-(6-amino-5-ethylpyrimidin-4-yl)piperidin-4-yl)-1-(2-(azetidin-1-yl)ethyl)-1H-imidazol-4-yl)-2-fluorobenzamideas a by product. LC-MS: (M+1=505, obsd.=505).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“108”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=480, obsd.=480).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(isoxazol-4-yl)pyrimidin-4-amine(“109”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amineof using isoxazol-4-ylboronic acid instead tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.LC-MS: (M+1=557, obsd.=557).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrrol-3-yl)pyrimidin-4-amine(“110”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amineof using (1H-pyrrol-3-yl)boronic acid instead tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.LC-MS: (M+1=555, obsd.=555).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-methylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“111”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-methylpyridineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=447, obsd.=447).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-methoxypyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“112”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-methoxypyridineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=463, obsd.=463).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-methylpyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“113”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amineof using3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-methylpyridineinstead of3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridinehydrochloride salt. LC-MS: (M+1=447, obsd.=447).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropylpyrimidin-4-amine(“114”)

A reaction mixture of 6-Chloro-5-isopropyl-pyrimidin-4-ylamine (30.00mg; 0.17 mmol; 1.00 eq.),4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate (2) (109.16 mg; 0.17 mmol; 1.00 eq.), and Cs₂CO₃(227.81 mg; 0.70 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C.for 4 days, purified by prep HPLC, collected title compound 31 mg, yield27.7%. LC-MS: (M+1=532, obsd.=532).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine(“115”)

A reaction mixture of 6-Chloro-5-methoxy-pyrimidin-4-ylamine (45.00 mg;0.28 mmol; 1.00 eq.),4-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridinehydrochloride (4) (148.13 mg; 0.28 mmol; 1.00 eq.), and Cs₂CO₃ (367.53mg; 1.13 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2days, purified by HPLC collected title compound 17 mg. LC-MS: (M+1=503,obsd.=503).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethoxypyrimidin-4-amine(“116”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amineusing 6-Chloro-5-etythoxy-pyrimidin-4-ylamine instead of6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=517, obsd.=517).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine(“117”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amineusing 6-chloro-5-isopropoxypyrimidin-4-amine instead of6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=531, obsd.=531).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine(“118”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amineusing 6-chloro-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine instead of6-Chloro-5-methoxy-pyrimidin-4-ylamine. LC-MS: (M+1=571, obsd.=571).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“119”)

A reaction mixture of 6-Chloro-5-ethyl-pyrimidin-4-ylamine (30.00 mg;0.19 mmol; 1.00 eq.),2-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-6-trifluoromethyl-pyridinehydrochloride (4) (99.99 mg; 0.19 mmol; 1.00 eq.), and Cs₂CO₃ (248.09mg; 0.76 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for overweekend. Purified by HPLC (basic) to afford the title compound 38 mg,yield 32.7%. LC-MS (M+1=501, obsd.=501).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“120”)

A reaction mixture of 4-Amino-6-chloro-pyrimidine-5-carbonitrile (52.00mg; 0.36 mmol; 1.00 eq.),4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methoxy-phenyl)-1H-imidazol-2-yl]-piperidinehydrochloride (4) (179.46 mg; 0.36 mmol; 1.00 eq.), andEthyl-diisopropyl-amine (0.26 ml; 1.42 mmol; 4.00 eq.) in acetonitrile 2ml was stirred at RT for overnight, all starting material was convertedto desired monitored by Ic-MS, filtered, collected white solid as titlecompound, 106 mg, yield 62.5%. LC-MS (M+1=477, obsd.=477).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“121”)

A reaction mixture of4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(100.00 mg; 0.21 mmol; 1.00 eq.), DMSO 8 ml was stirred at RT added H₂O₂(0.20 ml; 2.10 mmol; 10.00 eq.) and 2.0M NaOH. 2.0M NaOH aq (1.05 ml;2.10 mmol; 10.00 eq.), stirred at RT for 2 hr, got desired as majordetected by Ic-ms, purified the product by prep HPLC (basic), titlecompound 66 mg, 63%. LC-MS (M+1=495, obsd.=495).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“122”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrileof using4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidineinstead4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methoxy-phenyl)-1H-imidazol-2-yl]-piperidinehydrochloride.

LC-MS: (M+1=461, obsd.=461).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(6-chloropyridin-2-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“123”)

A reaction mixture of 6-Chloro-5-ethyl-pyrimidin-4-ylamine (45.00 mg;0.29 mmol; 1.00 eq.),2-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-6-chloropyridinehydrochloride (4) (140.40 mg; 0.29 mmol; 1.00 eq.), and Cs₂CO₃ (372.13mg; 1.14 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2days, purified by HPLC, collected title compound 36 mg. LC-MS (M+1=467,obsd.=467).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“124”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=479, obsd.=479).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“125”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=498, obsd.=498).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-bromopyrimidin-4-amine(“126”)

A reaction mixture of 5-Bromo-6-chloro-pyrimidin-4-ylamine (53.00 mg;0.25 mmol; 1.00 eq.),4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridinehydrochloride (4) (133.56 mg; 0.25 mmol; 1.00 eq.), andethyl-diisopropyl-amine (0.23 ml; 1.27 mmol; 5.00 eq.) in ACN 3 ml wasstirred at 80° C. for overnight. Purified by HPLC (basic), collectedtitle compound, 30 mg, yield, 21%. LC-MS: (M+1=551, obsd.=551).

5-bromo-6-(4-(1-(2-((3-chloropropyl)amino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“127”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-bromopyrimidin-4-amine.LC-MS: (M+1=588, obsd.=588).

4-amino-6-(4-(1-(2-aminoethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxylicacid (“128”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=516, obsd.=516).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(furan-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“129”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=419, obsd.=419).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“130”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=435, obsd.=435).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“131”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=429, obsd.=429).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(isoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“132”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=420, obsd.=420).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(furan-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“133”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=437, obsd.=437).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(thiophen-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“134”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=453, obsd.=453).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(isoxazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“135”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=437, obsd.=437).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-phenyl-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“136”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=447, obsd.=447).

4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“137”)

Step 1: 3-Methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butylester

To a solution of 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (2000.00 mg; 10.68 mmol; 1.00 eq.) in DCM 10 ml addedethyl-diisopropyl-amine (2.49 ml; 13.89 mmol; 1.30 eq.), then addeddropwise methanesulfonyl chloride (0.89 ml; 11.22 mmol; 1.05 eq.) at 00,the reaction mixture was stirred for overnight at RT. TLC (EA/HEX=7:3)showed staring material converted to desired completed.

Diluted the reaction solution with EA, washed with brine, organic layerwas dried, filtered through silica gel 10 g, most color material wasabsorbed on silica gel, the filtrate was evaporated off solvent, gotresidue as title compound directly using for the next step reaction, TLCwas clean.

Step 2: Benzyl4-(1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate

To a solution of4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid benzyl ester (1000.00 mg; 2.24 mmol; 1.00 eq.) in DMF 8 ml addedNaH (107.27 mg; 2.68 mmol; 1.20 eq.), stirred at RT for 20 mins, added3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester(1186.02 mg; 4.47 mmol; 2.00 eq.), the reaction mixture was stirred 85°C. for 5 hr, Ic-ms showed around 40% desired, continued stirring forover night, no big changed, purified the product by HPLC (basic) with30-100% acetonitrile/water, collected title compound 220 mg, yield 16%.

Step 3: tert-butyl3-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)pyrrolidine-1-carboxylate

To a solution of4-[1-(1-tert-butoxycarbonyl-pyrrolidin-2-ylmethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid benzyl ester (200.00 mg; 0.32 mmol; 1.00 eq.) in methanol 5 mladded trifluoro-acetic acid (54.24 mg; 0.48 mmol; 1.50 eq.), stirred atRT for 5 min, added ammonium formate (199.96 mg; 3.17 mmol; 10.00 eq.)and 200 mg wet 10% Pd/C, stirred at RT for 1 hr, Ic-ms showed cleandesired. Removed off solvent, added EA 50 ml, washed with Brine and 5%NaHCO₃, dried, removed off solvent, got title compound 110 mg, yield70%.

Step 4: tert-butyl3-(2-(1-(6-amino-5-cyanopyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)pyrrolidine-1-carboxylate

3-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (109.27 mg; 0.23 mmol; 1.00 eq.) in acetonitrile 2ml was added ethyl-diisopropyl-amine (0.08 ml; 0.45 mmol; 2.00 eq.) and4-amino-6-chloro-pyrimidine-5-carbonitrile (35.00 mg; 0.23 mmol; 1.00eq.), the reaction mixture was stirred at RT for 1 hr, Ic-ms showeddesired as major product, removed off solvent, got residue, which astitle compound directly using for the next step reaction.

Step 5:4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrileTert-butyl3-(2-(1-(6-amino-5-cyanopyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)pyrrolidine-1-carboxylate

21.00 mg in 0.5 ml of methanol was added 0.5 ml of 4.0M HCl in dioxane,stirred at RT for 3 hrs, LC-MS showed desired. Purified by prep HPLC,collected title compound. LC-MS: (M+1=501, obsd.=501).

4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“138”)

Step 1: tert-butyl3-(2-(1-(6-amino-5-carbamoylpyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)pyrrolidine-1-carboxylate

A reaction mixture of3-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (100.00 mg; 0.17 mmol; 1.00 eq.) and 2.0N NaOHaq(0.83 ml; 1.66 mmol; 10.00 eq.), in DMSO 8 ml was stirred at RT for 5mins, added H₂O₂ (0.16 ml; 1.66 mmol; 10.00 eq.) stirred at RT for 2 hr.Purified the product by HPLC (basic), collected title compound 45 mg,yield 43%.

Step 2:4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide

3-[2-[1-(6-amino-5-carbamoyl-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (60.00 mg; 0.10 mmol; 1.00 eq.) in 0.5 ml methanolwas added 0.5 ml 4.0M HCl in dioxane, stirred at RT for 3 hrs, showeddesired by Ic-ms, removed off solvent, got white solid 52.5 mg as titlecompound. LC-MS: (M+1=519, obsd.=519).

6-(4-(1-(2-aminoethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“139”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=478, obsd.=478).

4-amino-6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“140”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=519, obsd.=519).

4-amino-6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“141”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=501, obsd.=501).

4-amino-6-(4-(1-(azetidin-3-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“142”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=487, obsd.=487).

4-amino-6-(4-(1-(azetidin-3-yl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“143”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=505, obsd.=505).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-chloropyrimidin-4-amine(“144”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=507, obsd.=507).

4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(1H-pyrazol-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“145”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=437, obsd.=437).

(S)-4-amino-6-(4-(1-(azetidin-2-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“146”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=501, obsd.=501).

4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“147”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=515, obsd.=515).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-chloropyrimidin-4-amine(“148”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=510, obsd.=510).

(S)-6-(4-(1-(azetidin-2-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-chloropyrimidin-4-amine(“149”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=510, obsd.=510).

(S)-4-amino-6-(4-(1-(azetidin-2-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“150”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=519, obsd.=519).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“151”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=504, obsd.=504).

(S)-6-(4-(1-(azetidin-2-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“152”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=504, obsd.=504).

4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“153”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=533, obsd.=533).

4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(piperidin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“154”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=533, obsd.=533).

4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(piperidin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“155”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=515, obsd.=515).

4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-((1-methylazetidin-3-yl)methyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“156”)

To a solution of4-amino-6-{4-[1-azetidin-3-ylmethyl-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide trifluoroacetate (2) (25.00 mg; 0.03 mmol; 1.00 eq.) inethanol 1 ml added formic acid (0.001 ml; 0.08 mmol; 2.50 eq.) andformaldehyde (0.001 ml; 0.04 mmol; 1.20 eq.), stirred at 65° C. for 3hr. Ic-ms showed clean desired peak. Removed off solvent, purified byHPLC, collected title compound 14.8 mg. LC-MS (M+1=533, obsd.=533).

5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(piperidin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“157”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=518, obsd.=518).

4-amino-6-(4-(1-(2-aminoethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“158”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=475, obsd.=475).

4-amino-6-(4-(1-(2-aminoethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide(“159”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=493, obsd.=493).

2-(2-(1-(6-amino-5-(1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-1-yl)ethanol(“160”)

Step 1:4-[4-(4-Fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-[4-Bromo-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (2000.00 mg; 5.34 mmol; 1.00 eq.),2-(4-fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(1233.97 mg; 8.02 mmol; 1.50 eq.), (273.09 mg; 0.53 mmol; 0.10 eq.) andCs₂CO₃ (3483 mg, 10.69 mmol) in dioxane 15 ml and water 1.5 ml waspurged with argon, added Pd(0)(tBu₃)₂ (273 mg, 0.53 mmol), stirred at50° C. for overnight. LC-MS showed desired as major product. Dilutedreaction solution with EA 70 ml, washed with brine 30 ml×2, separatedout organic layer, dried, removed off solvent, got crude product, whichwas subjected to biotage NASP column (100 g), elated with 40-100% EA inhexane and contained 0.5% TEA in EA, collected title compound 1650 mg,76%

Step 2:2-[4-(4-Fluoro-3-methyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethanolhydrochloride

To a solution of4-[4-(4-Fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (1600.00 mg; 3.97 mmol; 1.00 eq.) in methanol 10ml added 4.0M HCl in dioxane (9.91 ml; 39.65 mmol; 10.00 eq.), thereaction mixture was stirred at RT for 3 hrs, Ic-ms showed cleandesired, removed off solvent, got white solid as title compound.

Step 3:2-(2-(1-(6-amino-5-bromopyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-1-yl)ethanol

A reaction mixture of 5-bromo-6-chloro-pyrimidin-4-ylamine (370.00 mg;1.78 mmol; 1.00 eq.),2-[4-(4-fluoro-3-methyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethanolhydrochloride (3) (732.67 mg; 1.78 mmol; 1.00 eq.), and Cs₂CO₃ (2313.40mg; 7.10 mmol; 4.00 eq.) in DMSO 10 ml, stirred at 100° C. forovernight, cooled, poured into water 60 ml, stirred for 15 mins,filtered, collected light yellow solid, which was washed with water,dried, got title compound, 750 mg, 88.9%.

Step 4: tert-butyl4-(4-amino-6-(4-(4-(4-fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-1-carboxylate

a mixture of2-[2-[1-(6-amino-5-bromo-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl]-ethanol(1333.00 mg; 2.80 mmol; 1.00 eq.),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (1237.31 mg; 4.21 mmol; 1.50 eq.), Cs₂CO₃ (548 mg,1.68 mmol) in doxane 10 ml and water 1 ml, purged with argon, addedPd(0) (tBu₃)₂ (143 mg, 0.28 mmol) stirred at 50° C. for overnight. LC-MSshowed desired as major product, removed off solvent, purified by prepHPLC (Basic), collected title compound 400 mg, 25.4%

Step 5:2-(2-(1-(6-amino-5-(1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-1-yl)ethanol

tert-butyl4-(4-amino-6-(4-(4-(4-fluoro-3-methylphenyl)-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-1-carboxylate(10.00 mg; 0.02 mmol) in 0.5 ml methanol was added 0.5 ml 4.0M HCl indioxane, stirred at RT for 3 hrs, showed clean desired by LC-MS. Removedoff solvent, got white solid as title compound.

LC-MS: (M+1=463, obsd.=463).

6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“161”)

Step 1: tert-butyl4-(4-amino-6-(4-(4-(4-fluoro-3-methylphenyl)-1-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-1-carboxylate

To a stirring solution of4-(4-amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylicacid tert-butyl ester (350.00 mg; 0.62 mmol; 1.00 eq.) in THF 5 ml addedethyl-diisopropyl-amine (0.28 ml; 1.56 mmol; 2.50 eq.), then added dropwised methanesulfonyl chloride (0.10 ml; 1.24 mmol; 2.00 eq.) at 0° C.,the reaction mixture was stirred at RT for 1 hr, LC-MS showed desired asmajor, and starting material disappeared, removed off solvent, directlycarried the crude product for next step reaction.

Step 2:6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine

4-(4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-yl)-pyrazole-1-carboxylicacid tert-butyl ester (100.00 mg; 0.16 mmol; 1.00 eq.) in seal tube wasadded THF 2 ml and cyclopropylamine (0.70 ml; 9.81 mmol; 62.84 eq.),stirred at 50° C. for overnight. LC-MS showed desired as major, purifiedproduct by HPLC, collected title compound 35 mg. LC-MS: (M+1=502,obsd.=502).

IC₅₀ 12.9 nM (p70S6K enzyme), 150 nM (AKT enzyme).

6-(4-(4-(4-fluoro-3-methylphenyl)-1-(2-(methylamino)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“162”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amineLC-MS: (M+1=476, obsd.=476).

6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“163”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amineLC-MS: (M+1=490, obsd.=490).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“164”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amineLC-MS: (M+1=502, obsd.=502).

6-(4-(1-(2-(tert-butylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“165”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amineLC-MS: (M+1=518, obsd.=518).

5-bromo-6-(4-(1-(2-(methylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“166”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=525, obsd.=525/527).

6-(4-(1-(2-(methylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“167”)

The title compound was a side product by preparing5-bromo-6-(4-(1-(2-(methylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=447, obsd.=447).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(isoxazol-4-yl)pyrimidin-4-amine(“168”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=540, obsd.=540).

4-amino-6-(4-(1-(2-(methylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“169”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=471, obsd.=471).

5-(4,5-dihydroisoxazol-4-yl)-6-(4-(1-(2-(methylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“170”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=516, obsd.=516).

5-ethyl-6-(4-(1-(2-(methylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“171”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=475, obsd.=475).

5-chloro-6-(4-(1-(2-(methylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“172”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=481, obsd.=481).

5-chloro-6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine(“173”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=507, obsd.=507).

6-(4-(1-(2-(ethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine(“174”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine.LC-MS: (M+1=536, obsd.=536).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine(“175”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=534, obsd.=534).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethoxypyrimidin-4-amine(“176”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=520, obsd.=520).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethoxypyrimidin-4-amine(“177”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine.LC-MS: (M+1=480, obsd.=480).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine(“178”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine.LC-MS: (M+1=494, obsd.=494).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-isopropylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“179”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=475, obsd.=475).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-isopropylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-chloropyrimidin-4-amine(“180”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=481, obsd.=481).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-isopropylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-bromopyrimidin-4-amine(“181”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=525, obsd.=525/527).6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-isopropylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-vinylpyrimidin-4-amine(“182”)

a mixture of6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine(70.00 mg; 0.13 mmol; 1.00 eq.),4,4,5,5-Tetramethyl-2-vinyl-[1,3,2]dioxaborolane (0.03 ml; 0.16 mmol;1.20 eq.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (4.77 mg;0.01 mmol; 0.07 eq.) and in doxane 15 ml and water 1.5 ml, stirred at 50C for overnight.

LC-MS showed desired as major product, purified by HPLC, collected titlecompound. LC-MS: (M+1=473, obsd.=473).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-vinylpyrimidin-4-amine(“183”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-isopropylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-vinylpyrimidin-4-amine.LC-MS: (M+1=502, obsd.=502).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-methoxypyrimidin-4-amine(“184”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=451, obsd.=451).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethoxypyrimidin-4-amine(“185”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=466, obsd.=466).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine(“186”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=520, obsd.=520).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine(“187”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=480, obsd.=480).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine(“188”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=450, obsd.=450).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropylpyrimidin-4-amine(“189”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=464, obsd.=464).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-bromopyrimidin-4-amine(“190”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=515, obsd.=515/517).4-amino-6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile(“191”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=447, obsd.=447).

6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-chloro-N-methylpyrimidin-4-amine(“192”)

A reaction mixture of 5,6-Dichloro-pyrimidin-4-yl)-methyl-amine (30.00mg; 0.17 mmol; 1.00 eq.),4-[1-(2-azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridinehydrochloride (4) (97.37 mg; 0.19 mmol; 1.10 eq.), andEthyl-diisopropyl-amine (219.63 mg; 0.67 mmol; 4.00 eq.) in DMSO 1 mlwas stirred at 100° C. for overnight. Purified by HPLC, collected titlecompound. LC-MS: (M+1=521, obsd.=521).

(6-{4-[1-Azetidin-3-ylmethyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-chloro-pyrimidin-4-yl)-methyl-amine(“193”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=470, obsd.=470).

6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)cyclohexyl)-5-isopropylpyrimidin-4-amine(“194”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=464, obsd.=464).

5-Ethyl-6-{4-[4-(4-fluoro-phenyl)-1-(2-morpholin-4-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“195”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=480, obsd.=480).

6-{4-[4-(3,4-Difluoro-phenyl)-1-(2-morpholin-4-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“196”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=498, obsd.=498).

5-Ethyl-6-(4-{4-(4-fluoro-phenyl)-1-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidin-4-ylamine(“197”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=492, obsd.=492).

6-(4-{4-(3,4-Difluoro-phenyl)-1-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-5-ethyl-pyrimidin-4-ylamine(“198”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=510, obsd.=510).

6-(4-{4-(3,4-Difluoro-phenyl)-1-[2-(3-fluoro-azetidin-1-yl)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-5-ethyl-pyrimidin-4-ylamine(“199”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=486, obsd.=486).

5-Ethyl-6-{4-[1-[2-(3-fluoro-azetidin-1-yl)-ethyl]-4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“200”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=468, obsd.=468).

5-Ethyl-6-(4-{4-(4-fluoro-phenyl)-1-[2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidin-4-ylamine(“201”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=506, obsd.=506).

6-(4-{4-(3,4-Difluoro-phenyl)-1-[2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-5-ethyl-pyrimidin-4-ylamine(“202”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=524, obsd.=524).

6-(4-{4-(3,4-Difluoro-phenyl)-1-[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-5-ethyl-pyrimidin-4-ylamine(“203”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=510, obsd.=510).

5-Ethyl-6-(4-{4-(4-fluoro-phenyl)-1-[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidin-4-ylamine(“204”)

The title compound was prepared in an analogous manner as5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine.LC-MS: (M+1=492, obsd.=492).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(5-chloro-6-fluoro-pyridin-3-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“205”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=482, obsd.=482).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(2-fluoro-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“206”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=448, obsd.=448).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(1H-indazol-5-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“207”)

The title compound was prepared in an analogous manner as4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide.LC-MS: (M+1=469, obsd.=469).

6-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“208”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=532, obsd.=532).

5-Chloro-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“209”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=538, obsd.=538).

5-Chloro-6{4-(4-hydroxy-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“210”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-hydroxy-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=536, obsd.=536).

5-Fluoro-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“211”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=522, obsd.=522).

6-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropylene-pyrimidin-4-ylamine(“212”)

The title compound was prepared in an analogous manner5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=558, obsd.=558).

6-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropylene-pyrimidin-4-ylamine(“213”)

The title compound was prepared in an analogous manner5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=544, obsd.=544).

6-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“214”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=504, obsd.=504).

6-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-methyl-pyrimidin-4-ylamine(“215”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=518, obsd.=518).

5-Chloro-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“216”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=552, obsd.=552).

5-Bromo-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-azetidin-1-yl}-pyrimidin-4-ylamine(“217”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=568, obsd.=568).

5-Chloro-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-azetidin-1-yl}-pyrimidin-4-ylamine(“218”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=524, obsd.=524).

5-(4-fluorophenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“219”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=584, obsd.=584).

5-vinyl-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“220”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=516, obsd.=516).

6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“221”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=490, obsd.=490).

5-(4-methylcarboxyesterphenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“222”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=624, obsd.=624).

5-(4-methylcarboxyesterphenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“223”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=638, obsd.=638).

5-(4-carboxyacidphenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“224”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=610, obsd.=610).

5-(4-carboxy acidphenyl)-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“225”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=624, obsd.=624).

5-Bromo-6{4-(3,4-difluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“226”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3,4-difluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=532, obsd.=532).

5-Bromo-6{4-(4-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“227”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=514, obsd.=514).

5-Bromo-6{4-(3-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“228”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=514, obsd.=514).

5-Bromo-6{4-(3-fluoro-4-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“229”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=582, obsd.=582).

5-Ethyl-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“230”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=518, obsd.=518).

5-Ethyl-6{4-(3-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“231”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=464, obsd.=464).

5-Ethyl-6{4-(4-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“232”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=464, obsd.=464).

5-Ethyl-6{4-(3,4-difluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“233”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3,4-difluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=482, obsd.=482).

5-Ethyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“234”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=532, obsd.=532).

5-Chloro-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“235”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=538, obsd.=538).

5-Chloro-6{4-(3-fluoromethylphenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“236”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=470, obsd.=470).

5-Chloro-6{4-(4-fluoromethylphenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“237”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=470, obsd.=470).

5-Chloro-6{4-(3,4-difluoromethylphenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“238”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3,4-difluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=488, obsd.=488).

5-Vinyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“239”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=530, obsd.=530).

5-Vinyl-6{4-(3-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“240”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=462, obsd.=462).

5-Vinyl-6{4-(4-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“241”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=462, obsd.=462).

5-Vinyl-6{4-(3,4-difluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“242”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3,4-difluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=480, obsd.=480).

6{4-(3,4-difluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“243”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3,4-difluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=454, obsd.=454).

6{4-(3-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“244”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluorophenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=436, obsd.=436).

5-Ethyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-((S)-3-fluoro-pyrrolidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“245”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-((S)-3-fluoro-pyrrolidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=550, obsd.=550).

5-Ethyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-((R)-3-fluoro-pyrrolidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“246”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-((S)-3-fluoropyrrolidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=550, obsd.=550).

5-Ethyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-(4,4-difluoro-piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“247”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-(4,4-difluoropiperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=582, obsd.=582).

5-Ethyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-(3,3-difluoro-piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (“248”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-(3,3-difluoro-piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=582, obsd.=582).

5-Ethyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-(4-fluoro-piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“249”)

The title compound was prepared in an analogous manner5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-(4-fluoro-piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=564, obsd.=564).

5-Ethyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-(3-fluoro-piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“250”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-3-trifluoromethyl-phenyl)-1-(2-(3-fluoro-piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=564, obsd.=564).

5-Ethyl-6{4-(3-fluoro-4-chlorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“251”)

The title compound was prepared in an analogous manner5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-chloro-3-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=498, obsd.=498).

5-Ethyl-6{4-(4-fluoro-3-chlorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“252”)

The title compound was prepared in an analogous manner5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=498, obsd.=498).

5-cyclobutyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-(piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“253”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-3-trifluoromethyl-phenyl)-1-(2-(piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=572, obsd.=572).

5-cyclobutyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“254”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=558, obsd.=558).

5-cyclobutyl-6{4-(3,4-difluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“255”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3,4-difluoro-1-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=508, obsd.=508).

5-cyclobutyl-6{4-(4-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“256”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=490, obsd.=490).

5-cyclobutyl-6{4-(3-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“257”)

The title compound was prepared in an analogous manner5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=490, obsd.=490).

5-cyclobutyl-6{4-(3-fluoro-4-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“258”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=558, obsd.=558).

5-cyclobutyl-6{4-(4-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“259”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=540, obsd.=540).

5-cyclobutyl-6{4-(4-chloro-3-fluoro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“260”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-chloro-3-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=525, obsd.=525).

5-cyclobutyl-6{4-(3-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“261”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=540, obsd.=540).

5-cyclobutyl-6{4-(3-chloro-4-fluoro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“262”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=525, obsd.=525).

5-cyclobutyl-6{4-(4-chloro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“263”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-chloro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=507, obsd.=507).

5-cyclobutyl-6{4-(3-chloro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“264”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=507, obsd.=507).

5-Bromo-6{4-(4-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“265”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=565, obsd.=565).

5-Bromo-6{4-(4-chloro-3-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“266”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-chloro-3-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=549, obsd.=549).

5-Bromo-6{4-(3-trifluoromethyl-phenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“267”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=565, obsd.=565).

5-Bromo-6{4-(3-chloro-4-fluorophenyl)-1-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“268”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=549, obsd.=549).

5-vinyl-6{4-(4-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“269”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=512, obsd.=512).

6{4-(4-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“270”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=486, obsd.=486).

5-Ethyl-6{4-(4-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“271”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=514, obsd.=514).

5-Ethyl-6{4-(3-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“272”)

The title compound was prepared in an analogous manner manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=514, obsd.=514).

5-Ethyl-6{4-(4-chloro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“273”)

The title compound was prepared in an analogous manner manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-chloro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=481, obsd.=481).

5-Ethyl-6{4-(3-chloro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“274”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=481, obsd.=481).

5-Ethyl-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-((3,3-difluoro-pyrrolidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“275”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-(3,3-difluoro-pyrrolidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=568, obsd.=568).

5-Ethyl-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-((piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“276”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-(piperidin-1-yl)-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=546, obsd.=546).

5-Ethyl-6{4-(3-trifluoromethyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“277”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=500, obsd.=500).

5-Ethyl-6{4-(3-fluoro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“278”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-fluoro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=450, obsd.=450).

5-Ethyl-6{4-(3-chloro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“279”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=467, obsd.=467).

5-cyclobutyl-6{4-(3-fluoro-4-trifluoromethylphenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“280”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=544, obsd.=544).

5-Ethyl-6{4-(4-fluoro-3-chlorophenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“281”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-chloro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=584, obsd.=584).

5-Ethyl-6{4-(3,4-difluorophenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“282”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3,4-difluoro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=568, obsd.=568).

5-Nitro-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“283”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=535, obsd.=535).

5-Amino-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“284”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=505, obsd.=505).

5-Formyl-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“285”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=518, obsd.=518).

6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine-5-carboxyacid (“286”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=548, obsd.=548).

5-Formyl-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“287”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=532, obsd.=532).

5-Ethylamide-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“288”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=547, obsd.=547).

5-Ethoxy-6{4-(3-chloro-4-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“289”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=515, obsd.=515).

5-isopropoxy-6{4-(3-chloro-4-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“290”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=529, obsd.=529).

5-Ethoxy-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(N,N-dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“291”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-(N,N-dimethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=522, obsd.=522).

5-Isopropoxy-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(N,N-dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“292”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-(N,N-dimethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=536, obsd.=536).

5-Ethoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“293”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-dimethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=468, obsd.=468).

5-isopropoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“294”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-dimethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=482, obsd.=482).

5-Ethyl-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“295”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-dimethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=452, obsd.=452).

5-Ethyl-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-diethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“296”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-diethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=480, obsd.=480).

5-Ethyl-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“297”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=478, obsd.=478).

5-Ethoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“298”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=494, obsd.=494).

5-Isopropoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“299”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=508, obsd.=508).

5-Ethyl-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-isopropylethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“300”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-isopropylethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=494, obsd.=494).

5-Ethoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-isopropylethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“301”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-isopropylethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=510, obsd.=510).

5-Isopropoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-isopropylethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“302”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-isopropylethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=524, obsd.=524).

5-Ethoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-diethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“303”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-diethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=496, obsd.=496).

5-Isopropoxy-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-diethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“304”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-(N,N-diethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=510, obsd.=510).

4-amino-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“305”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=529, obsd.=529).

4-amino-6{4-(3,4-difluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“306”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(3,4-difluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=479, obsd.=479).

4-amino-6{4-(3-chloro-4-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“307”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-fluoro-3-chloro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=496, obsd.=496).

4-amino-6{4-(4-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“308”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=461, obsd.=461).

4-amino-6{4-(3-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“309”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(3-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=461, obsd.=461).

4-amino-6{4-(3-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“310”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=511, obsd.=511).

4-amino-6{4-(3-chloro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“311”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(3-chloro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=478, obsd.=478).

4-amino-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“312”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=543, obsd.=543).

4-amino-6{4-(3,4-difluorophenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“313”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(3,4-fluoro-3-difluoro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=465, obsd.=465).

4-amino-6{4-(4-fluoro-3-difluoromethoxy-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“314”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-fluoro-3-difluoromethoxy-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=513, obsd.=513).

4-amino-6{4-(2-oxo-1,2-dihydro-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“315”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=446, obsd.=446).

4-amino-6{4-(4-methyl-3-trifluoromethyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“316”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methyl-3-trifluoromethyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=511, obsd.=511).

4-amino-6{4(2-isopropyl-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“317”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(2-isopropyl-pyridin-4-yl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=472, obsd.=472).

4-amino-6{4(2-ethyl-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“318”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(2-ethyl-pyridin-4-yl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=458, obsd.=458).

4-amino-6{4(2-cyclopropyl-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“319”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(2-cyclopropyl-pyridin-4-yl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=470, obsd.=470).

4-amino-6{4-(4-methyl-3-fluoro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“320”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methyl-3-fluoro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=461, obsd.=461).

4-amino-6{4-(4-methoxy-3-fluoro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“321”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methoxy-3-fluoro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=477, obsd.=477).

4-amino-6{4-(4-methyl-3-chloro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“322”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methyl-3-chloro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=478, obsd.=478).

4-amino-6{4-(4-methoxy-3-chloro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“323”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methoxy-3-chloro-phenyl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=494, obsd.=494).

4-amino-6{4-(3-methyl-4-fluoro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“324”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methyl-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=475, obsd.=475).

4-amino-6{4-(3-methyl-4-fluoro-phenyl)-1-2-(N,N-dimethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“325”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methyl-4-fluoro-phenyl)-1-(2-(N,N-dimethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=449, obsd.=449).

4-amino-6{4-(3-methyl-4-fluoro-phenyl)-1-2-(N,N-diethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“326”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methyl-4-fluoro-phenyl)-1-(2-(N,N-diethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=477, obsd.=477).

4-amino-6{4-(3-methyl-4-fluoro-phenyl)-1-2-(N,N-isopropylethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile(“327”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing4-[4-(4-methyl-4-fluoro-phenyl)-1-(2-(N,N-isopropylethylamino)-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(3,4-difluoro-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS:(M+1=491, obsd.=491).

4-amino-6{4-(3,4-difluorophenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“328”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-ethyl)-4-(3,4-difluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=483, obsd.=483).

4-amino-6{4-(3,4-difluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“329”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(3,4-difluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=498, obsd.=498).

4-amino-6{4-(3-chloro-4-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“330”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=515, obsd.=515).

4-amino-6{4-(4-fluoro-3-trifluoromethylphenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“331”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(3-fluoro-4-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=548, obsd.=548).

4-amino-6{4(2-isopropyl-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“332”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(2-isopropyl-pyridin-4-yl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=490, obsd.=490).

4-amino-6{4-(4-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“333”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=479, obsd.=479).

4-amino-6{4-(3-fluorophenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“334”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(3-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=479, obsd.=479).

4-amino-6{4-(3-trifluoromethyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“335”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=529, obsd.=529).

4-amino-6{4-(3-chloro-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“336”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(3-chloro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=496, obsd.=496).

4-amino-6{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-2-(piperidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“337”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=561, obsd.=561).

4-amino-6{4-(4-fluoro-3-difluoromethoxy-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“338”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(4-fluoro-3-difluoromethoxy-phenyl)-1-(2-azetidine-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=531, obsd.=531).

4-amino-6{4-(2-oxo-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“339”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(2-oxo-pyridin-4-yl)-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-difluoromethoxy-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=464, obsd.=464).

4-amino-6{4-(4-methyl-3-trifluoromethyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“340”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-ethyl)-4-(4-methyl-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=529, obsd.=529).

4-amino-6{4(2-ethyl-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“341”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(2-ethyl-pyridin-4-yl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=476, obsd.=476).

4-amino-6{4(2-cyclopropyl-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“342”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(2-cyclopropyl-pyridin-4-yl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=488, obsd.=488).

4-amino-6{4(2-tert-butyl-pyridin-4-yl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“343”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-[4-(2-tert-butyl-pyridin-4-yl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=504, obsd.=504).

4-amino-6{4-(4-methyl-3-fluoro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“344”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-ethyl)-4-(4-methyl-3-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=479, obsd.=479).

4-amino-6{4-(4-methoxy-3-fluoro-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“345”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-ethyl)-4-(4-methoxy-3-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=495, obsd.=495).

4-amino-6{4-(3-chloro-4-methyl-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“346”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-ethyl)-4-(3-chloro-4-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=496, obsd.=496).

4-amino-6{4-(3-chloro-4-methoxy-phenyl)-1-2-(azetidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“347”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-ethyl)-4-(3-chloro-4-methoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=512, obsd.=512).

4-amino-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-dimethylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“348”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-(N,N-dimethylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=467, obsd.=467).4-amino-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-diethylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“349”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-(N,N-diethylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=495, obsd.=495).

4-amino-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“350”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-(pyrrolidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=493, obsd.=493).

4-amino-6{4-(4-fluoro-3-methyl-phenyl)-1-2-(N,N-ethylisopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxylicacid amide (“351”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-(N,N-ethylisopropylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=509, obsd.=509).

6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-dimethylamino-pyrimidin-5-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“352”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing{5-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-pyrimidin-2-yl}-dimethyl-amineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=477, obsd.=477).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(2-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“353”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-fluoro-phenyl)-1H-imidazol-2-yl]-piperidineinstead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=447, obsd.=447).

3-[2-[1-(6-Amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-1-(2-azetidin-1-yl-ethyl)-1H-imidazol-4-yl]-benzenesulfonamide(“354”)

The title compound was prepared in an analogous manner as5-bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing3-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-benzenesulfonamidetrifluoroacetate instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=508, obsd.=508).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-methanesulfonyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“355”)

The title compound was prepared in an analogous manner as5-bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing4-[1-(2-Azetidin-1-yl-ethyl)-4-(3-methanesulfonyl-phenyl)-1H-imidazol-2-yl]-piperidinetrifluoroacetate instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=507, obsd.=507).

4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-methanesulfonyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“356”)

The title compound was prepared in an analogous manner as4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-methanesulfonyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=525, obsd.=525).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“357”)

The title compound was prepared in an analogous manner as5-bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing2-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethanoltrifluoroacetate instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=476, obsd.=476).

4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“358”)

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(22.8 mg; 0.47 mmol; 1.00 eq) was dissolved in dichloromethane (10.00mL) and chilled to −78° C. The solution was charged with triethylamine(0.20 mL; 1.41 mmol; 3.00 eq) and methanesulfonyl chloride (0.05 mL;0.70 mmol; 1.50 eq). The reaction was stirred, cold, for 1 hour, thenallowed to warm to ambient temperature. The reaction mixture wasquenched by dropwise addition of sodium bicarbonate (saturated aq; 10mL). The organic layer was separated, dried over sodium sulphate,filtered and concentrated to yield methanesulfonic acid2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethylester (259 mg; 0.47 mmol; 99.8%). LC-MS: (M+1=554, obsd.=554).

The title compound was prepared by stirring methanesulfonic acid2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethylester (85.0 mg; 0.15 mmol; 1.00 eq) in cyclopropylmethylamine (54.6 mg,0.77 mmol; 5.0 eq) at ambient temperature. The reaction mixture waspurified via flash chromatography using a gradient of 0-10% methanol indichloromethane to give4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(32.7 mg; 0.06 mmol; 40.3%). LC-MS: (M+1=529, obsd.=529).

4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“359”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=547, obsd.=547).

4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile(“360”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing N-isopropyl-N-methylamine instead of cyclopropylmethylamine.LC-MS: (M+1=531, obsd.=531).

4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carboxylicacid amide (“361”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=549, obsd.=549).

4-Amino-6-{4-[1-{2-[(2-dimethylamino-ethyl)-methyl-amino]-ethyl}-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“362”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing N,N,N′-trimethylethylenediamine instead of cyclopropylmethylamine.LC-MS: (M+1=560, obsd.=560).

4-Amino-6-[4-(4-(4-fluoro-3-trifluoromethyl-phenyl)-1-{2-[(2-methoxy-ethyl)-methyl-amino]-ethyl}-1H-imidazol-2-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile(“363”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing N-(2-methoxyethyl)methylamine instead of cyclopropylmethylamine.LC-MS: (M+1=547, obsd.=547).

4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile(“364”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing 2-methoxyethylamine instead of cyclopropylmethylamine. LC-MS:(M+1=533, obsd.=533).4-Amino-6-{4-[1-{2-[(2-dimethylamino-ethyl)-methyl-amino]-ethyl}-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“365”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=549, obsd.=549).

4-Amino-6-[4-(4-(4-fluoro-3-trifluoromethyl-phenyl)-1-{2-[(2-methoxy-ethyl)-methyl-amino]-ethyl}-1H-imidazol-2-yl)-piperidin-1-yl]-pyrimidine-5-carboxylicacid amide (“366”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-[4-(4-(4-fluoro-3-trifluoromethyl-phenyl)-1-{2-[(2-methoxy-ethyl)-methyl-amino]-ethyl}-1H-imidazol-2-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=565, obsd.=565).

4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carboxylicacid amide (“367”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=551, obsd.=551).

4-Amino-6-{4-[1-[2-(benzyl-methyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“368”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-[2-(benzyl-methyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=597, obsd.=597).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“369”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing isopropylamine instead of cyclopropylmethylamine. LC-MS: (M+1=517,obsd.=517).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“370”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=535, obsd.=535).

4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-1-methyl-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carboxylicacid amide (“371”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-1-methyl-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=565, obsd.=565).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“372”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing isobutylamine instead of cyclopropylmethylamine. LC-MS: (M+1=531,obsd.=531).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“373”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=549, obsd.=549).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“374”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=489,obsd.=489).

4-Amino-6-{4-[1-(2-tert-butylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“375”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing tert-butylamine instead of cyclopropylmethylamine. LC-MS:(M+1=531, obsd.=531).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“376”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=507, obsd.=507).

4-Amino-6-{4-[1-(2-tert-butylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“377”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-tert-butylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=549, obsd.=549).

4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“378”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing methanesulfonic acid2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl]-ethylester instead of methanesulfonic acid2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethylester. LC-MS: (M+1=475, obsd.=475).4-Amino-6-(4-{4-(4-fluoro-3-methyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile(“379”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing N-isobutyl-Nmethylamine instead of cyclopropylmethylamine. LC-MS:(M+1=477, obsd.=477).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“380”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing isopropylamine instead of cyclopropylmethylamine. LC-MS: (M+1=463,obsd.=463).

4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“381”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing cyclopentylamine instead of cyclopropylmethylamine. LC-MS:(M+1=543, obsd.=543).

4-Amino-6-{4-[1-[2-(1,1-dimethyl-propylamino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“382”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing tert-amylamine instead of cyclopropylmethylamine. LC-MS: (M+1=545,obsd.=545).

4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“383”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=493, obsd.=493).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“384”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing2-[4-(4-Fluoro-3-methyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethanoltrifluoroacetate instead of4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine.LC-MS: (M+1=422, obsd.=422).

4-Amino-6-(4-{4-(4-fluoro-3-methyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carboxylicacid amide (“385”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-(4-{4-(4-fluoro-3-methyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=495, obsd.=495).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“386”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=481, obsd.=481).

4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“387”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=561, obsd.=561).

4-Amino-6-{4-[1-[2-(1,1-dimethyl-propylamino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“388”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-[2-(1,1-dimethyl-propylamino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=563, obsd.=563).

4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“389”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing cyclopentylamine instead of cyclopropylmethylamine. LC-MS:(M+1=489, obsd.=489).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“390”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing isobutylamine instead of cyclopropylmethylamine. LC-MS: (M+1=477,obsd.=477).

4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“391”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=507, obsd.=507).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“392”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=495, obsd.=495).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“393”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=440, obsd.=440).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile(“394”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing methylamine instead of cyclopropylmethylamine. LC-MS: (M+1=435,obsd.=435).

4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“395”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=494, obsd.=494).

2-[2-[1-(6-Amino-5-ethoxy-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-yl]-ethanol(“396”)

The title compound was prepared in an analogous manner as5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamineusing 6-chloro-5-ethoxy-pyrimidin-4-ylamine instead of6-chloro-5-bromo-pyrimidin-4-ylamine. LC-MS: (M+1=441, obsd.=441).

4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“397”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamideusing4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileinstead of4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile.LC-MS: (M+1=453, obsd.=453).

5-Ethoxy-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“398”)

The title compound was prepared in an analogous manner as4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrileusing isopropylamine and methanesulfonic acid2-[2-[1-(6-amino-5-ethoxy-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethylester instead of cyclopropylmethylamine and methanesulfonic acid2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethylester. LC-MS: (M+1=536, obsd.=536).

{3-[2-[1-(6-Amino-5-isopropyl-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-methyl-phenyl)-imidazol-1-ylmethyl]-azetidin-1-yl}-methanol(“399”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=494, obsd.=494).

5-Ethyl-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(1-methyl-azetidin-3-ylmethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine(“400”)

The title compound was prepared in an analogous manner as6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine.LC-MS: (M+1=464, obsd.=464).

Biological Activity P70S6K Enzyme Assay

P70S6K inhibitor compounds are diluted and plated in 96 well plates. Areaction mixture including the following components is then added to thecompound plate to initiate the enzyme reaction; P70S6K (3 nM, T412Emutant, Millipore) is mixed with 24 μM ATP in an assay buffer containing100 mM Hepes (pH 7.5), 5 mM MgCl2, 1 mM DTT, 0.015% Brij and 1 μM of thesubstrate peptide FITC-AHA-AKRRRLSSLRA-OH (derived from the S6 ribosomalprotein sequence, FITC=fluorescein isothiocyanate, AHA=6-aminohexanoicacid). The reaction is incubated for 90 min at 25° C., before theaddition of 10 mM EDTA to stop the reaction. The proportion of substrateand product (phosphorylated) peptide is analysed on a Caliper LifeSciences Lab Chip 3000, using a pressure of −1.4 psi, and upstream anddownstream voltages of −3000 and −700 respectively. Product peaks areresolved before substrate peaks on the resulting chromatograms.

AKT Enzyme Assay

A TTP Mosquito liquid handling instrument is used to place 125 nl of theappropriate concentration of inhibitor in 100% DMSO (for a dose responsecurve calculation) into each well of a 384-well plate. To this reactioncomponents are added to a final volume of 12.5.1:

-   -   0.1 ng/μl His-AKT (Full Length), (Invitrogen, Part #P2999, Lot        #641228C).    -   160 uM ATP (Fluka, 02055)    -   1 mM DTT (Sigma, D0632)    -   1 mM MgCl2 (Sigma, M1028)    -   1 μM substrate peptide (sequence FITC-AHA-GRPRTSSFAEG-NH2),        synthesized by    -   Tufts Peptide Synthesis service.    -   100 mM HEPES pH 7.5 (Calbiochem, 391338)    -   0.015% Brij-35 (Sigma, B4184)

The reaction is incubated for 90 min at 25 C, and then stopped by theaddition of 70 μl of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35,10 mM EDTA (Sigma, E7889)).

The plate is read on a Caliper LC 3000 in an Off-Chip mobility shiftassay format, using the following parameters for a 12-sipper chip:screening pressure −2.3 psi, upstream voltage −500, and downstreamvoltage −3000. These conditions cause unphosphorylated substrate andphosphorylated product peptide to resolve as separate peaks allowingdirect measurement of percentage of conversion of substrate to product.The percent conversion can be plotted against concentration of inhibitorto produce a sigmoidal dose response curve, from which an IC50 can becalculated.

The values for the p70S6K and AKT enzyme inhibition assay for thecompounds set out in the Experimental section are presented in Table 4.

TABLE 4 p70S6K and AKT Enzyme Inhibition by Compound Described byFormula (I) and Formula (II) Compound IC₅₀ IC₅₀ No. p70S6K (nM) AKT (nM)1 2.1 66 2 57.0 — 3 6.2 1700 4 31.9 6100 5 315 — 6 0.6 160 7 1.5 110 81.8 9.1 9 2.1 440 10 3.4 2200 11 4.7 520 12 87 — 13 7.3 8300 14 1.9 25015 11 150 16 21 — 17 2.7 2.7 18 250 — 19 2.2 1700 20 7.1 2700 21 3.7 —22 1.6 — 23 3.0 — 24 5.3 — 25 190 — 26 1000 — 27 3.0 — 28 4.4 — 29 9.8 —30 6.3 — 31 7.5 — 32 4.2 — 33 2.7 — 34 12 — 35 9 — 36 2.2 1100 37 2.61600 38 3.5 84 39 1.4 860 40 2.3 2700 41 3 1400 42 5.4 — 43 1.7 600 442.4 9500 45 3.5 — 46 14 — 47 4.3 — 48 2.7 440 49 18.0 — 50 4.5 — 51 22.0— 52 5.0 — 53 2.3 880 54 2.5 740 55 2.1 850 56 3.5 14 57 8.2 140 58 3.775 59 9.6 110 60 2.5 6.8 61 2.8 9 62 18.0 350 63 5.1 130 64 8.7 85 655.5 12 66 110 410 67 2.2 9.3 68 7.3 230 69 3.0 43 70 3.5 180 71 5.6 45072 5.0 15 73 2.7 7.9 74 1.2 2.6 75 1.0 1.9 76 2.1 479 77 6.0 76 78 2.014 79 0.9 7.5 80 95 1400 81 98 15000 82 3.7 12 83 20 190 84 5.2 340 8512 43 86 1.9 4 87 9.3 190 88 8.1 95 89 7.3 33 90 3.1 31 91 3.2 4.8 924.2 71 93 3.0 7.7 94 13 1600 95 47 520 96 5.3 7.9 97 2.2 6.1 98 3 6.9 994.5 18 100 2.3 16 101 7.6 31 102 2.4 4.1 103 4.2 6.6 104 3.1 16.5 1052.7 13 106 21 49 107 98 160 108 2.2 4.8 109 0.9 1.6 110 0.7 1.9 111 8.7106 112 64.5 940 113 84 465 114 3.6 6.6 115 2.8 21 116 2.4 8.2 117 4.99.1 118 9.7 21 119 25 420 120 1.0 2.4 121 1.0 2.4 122 0.7 2.0 123 58 780124 2 14 125 1.5 9.7 126 0.5 2.2 127 1 2.8 128 5.5 90 129 11 250 130 2.691 131 5.7 165 132 23 220 133 46 3600 134 6 1900 135 860 760 136 8.41900 137 2.7 11 138 1.7 100 139 1.1 6.6 140 2.2 27 141 13 64.5 142 6.4240 143 16 670 144 1.1 2.5 145 53 2200 146 3.8 31 147 1.8 2.9 148 4.816.5 149 4.8 38 150 10 220 151 2.2 19 152 5.2 280 153 10 220 154 3 480155 0.9 160 156 4.9 81 157 2 190 158 1.5 3.6 159 1.5 15 160 6.7 670 16112.9 150 162 5.9 21 163 .73 4.8 164 4.4 5.5 165 2.8 5.5 166 1.3 1.5 167130 >1000 168 2.9 2.7 169 1.3 1.7 170 170 120 171 0.6 2.1 172 2.0 1.4173 2.8 3.6 174 0.44 0.52 175 5.9 4.5 176 5.5 5 177 1.2 2.1 178 3.9 2.7179 1.9 4.2 180 1.1 2.4 181 0.11 0.15 182 0.7 2.2 183 12 74 184 0.26 2.3185 2.2 6.6 186 2.0 7.1 187 3.4 6.4 188 2.1 2.3 189 1.1 4.5 190 0.1 0.1191 7.4 15 192 2700 7200 193 1300 5700 194 3.4 16 195 16 >1000 196 5.5370 197 6.3 130 198 11 255 199 12 385 200 21 640 201 16 >1000 202 9 89203 30 2500 204 37 3600 205 0.8 1.3 206 2.4 13 207 22 105 208 3.2 7.6209 3.1 2.2 210 3.7 3.0 211 23 23 212 6.7 16 213 7.9 20 214 50 180 2156.1 10 216 3.8 9 217 1.5 2.3 218 0.6 1 219 2.4 2.3 220 2.6 4.2 221 21 71222 11 43 223 21 78 224 5.7 12 225 5.8 12 226 1.3 1.7 227 1.4 2.9 2281.4 5.9 229 6.3 71 230 2.1 4.1 231 3.6 46 232 2.3 20 233 1.1 8.2 234 13470 235 10 1000 236 0.5 8.1 237 0.8 3.3 238 0.9 3.2 239 4.4 210 240 0.921 241 2.9 16 242 1.4 9.7 243 18 63 244 25 210 245 5.3 64 246 1.7 25 2475.5 520 248 16 1000 249 10 86 250 5.7 210 251 2.6 76 252 0.2 0.4 253 1928 254 8.1 9.1 255 6.9 9.4 256 6.5 11 257 4 20 258 36 380 259 37 430 26021 67 261 6.3 8.1 262 4 4.9 263 25 79 264 4.1 6.2 265 6.2 110 266 3.3 16267 2.2 4.2 268 1.4 1.8 269 10 190 270 360 1000 271 12 180 272 3.5 9.6273 7.4 190 274 1.5 12 275 2.8 430 276 2.8 9.3 277 3.2 18 278 4.6 79.5279 2.4 16 280 6 7.3 281 3.9 9.2 282 3.8 24 283 1.4 2.7 284 10.6 51.5285 1 1.4 286 135 730 287 0.6 1 288 21 190 289 0.8 2.1 290 1.3 2 291 2.68 292 3.4 7.6 293 1 1.7 294 1.3 1.9 295 4.1 23 296 1.6 2.6 297 3.9 6.6298 6.8 6.6 299 10 8.9 300 3.1 8.9 301 8.6 7.3 302 12 6.3 303 2.4 0.8304 4.6 2.6 305 1.9 3.2 306 2 7.6 307 0.8 1.5 308 2.6 13 309 2.6 21 3102.3 7.6 311 2.3 8.4 312 1.9 2.3 313 1.6 9.3 314 1.8 4.1 315 99 500 3160.8 24 317 1.7 11 318 1.4 15 319 1.7 23 320 1.6 48 321 2.6 59 322 1.3 13323 8.3 31 324 2.8 3.5 325 0.5 0.9 326 2.7 2.5 327 5.2 2.8 328 8.1 140329 14 120 330 3.6 14 331 4.6 15 332 3.8 37 333 21 380 334 26 620 335 1392 336 7.6 76 337 3.5 11 338 2 29 339 2700 5800 340 4 420 341 11 450 3423.7 61 343 5.5 170 344 25 2400 345 100 13000 346 3.9 220 347 87 990 3484 32 349 25 55 350 2.3 10 351 27 48 352 310 5700 353 14 140354 >10000 >10000 355 17 80 356 80 560 357 0.8 130 358 1.1 1.6 359 2.712 360 2.2 2.7 361 6.4 11 362 4.1 76 363 3.4 26 364 1.4 2.5 365 6.3 730366 9.2 440 367 4 67 368 21 760 369 3.6 5.4 370 0.9 2.5 371 18 85 3720.2 0.7 373 2.9 12 374 0.4 1.5 375 1.3 1.9 376 3.4 33 377 2 9.7 378 0.82.3 379 0.8 2.7 380 1.3 2.9 381 1.1 0.8 382 1.7 4.3 383 3.3 8.4 384 1.8440 385 6.2 42 386 2.4 15 387 1.4 8.4 388 2 13 389 0.9 0.7 390 1.9 1.4391 4 5.6 392 5.5 13 393 2.8 47 394 0.9 1.7 395 1.6 180 396 3.5 340 3972.5 16 398 2.1 1.5 399 2.5 56 400 0.06 --0.3

1-13. (canceled)
 14. A method for treating cancer, comprisingadministering to a subject a compound of Formula (I):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein: R¹ is Hal, LA, OH, O(LA), NH₂ and/or NH(LA),N(LA)₂, NO₂, CN, OCN, SCN, COOH, COO(LA), CONH₂, CONH(LA), CON(LA)₂,NHCO(LA), NHCONH(LA), NHCONH₂, NHSO₂(LA), CHO, CO(LA), SO₂NH₂, SO₂(LA),or a mono- or bicyclic, aliphatic or aromatic homo- or heterocyclehaving 0, 1, 2, 3 or 4 N, S and/or O atoms and 4, 5 or 6, 7, 8, 9, or 10skeleton atoms which may be unsubstituted or, independently of oneanother, mono-, di- or trisubstituted by Hal, LA, OH, O(LA), NH₂ and/orNH(LA), N(LA)₂, NO₂, CN, OCN, SCN, COOH, COO(LA), CONH₂, CONH(LA),CON(LA)₂, NHCO(LA), NHCONH(LA), NHCONH₂, NHSO₂(LA), CHO, CO(LA), SO₂NH₂,SO₂(LA) and/or SO₂Hal or an unbranched or branched linear or cyclicalkyl having 1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH₂groups may be replaced by an O atom and/or by an —NH—, NH(LA), —CO—,—NHCO— or —CH═CH— group, and/or in which a CH group may be replaced by—N—; R² is H, NH₂, NH(LA), N(LA)₂ or NHCO(LA); R³ is N or CH; R⁴ is H,an unbranched or branched linear or mono- or bicyclic alkyl group having1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or two CH₂ groups maybe replaced by an —O—, —NH—, group, and/or in which one or two CH groupsmay be replaced by —N—, and/or in which 1, 2 or 3 H atoms may bereplaced by Hal or OH, R⁵ is a monocyclic aromatic or aliphatic homo- orheterocycle having 0, 1 or 2 N, S and/or O atoms and 5 or 6 skeletonatoms which may be unsubstituted or, independently of one another,mono-, di- or trisubstituted by Hal, LA, OH, O(LA), NH₂ and/or NH(LA),N(LA)₂, NO₂, CN, OCN, SCN, COOH, COO(LA), CONH₂, CONH(LA), CON(LA)₂,NHCO(LA), NHCONH(LA), NHCONH₂, NHSO₂(LA), CHO, CO(LA), SO₂NH₂, SO₂(LA);Hal is F, Cl, Br or I, and LA is an unbranched or branched, saturated orpartially unsaturated, linear hydrocarbon chain having 1, 2, 3 or 4 Catoms, wherein 1, 2 or 3 H atoms may be replaced by Hal.
 15. The methodof claim 14, wherein said cancer is selected from the group consistingof brain, lung, colon, epidermoid, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, liver, ovarian, prostate,colorectal, uterine, rectal, oesophageal, testicular, gynecological,thyroid cancer, melanoma, hematologic malignancies such as acutemyelogenous leukemia, multiple myeloma, chronic myelogneous leukemia,myeloid cell leukemia, glioma and Kaposi's sarcoma.
 16. The method ofclaim 14, wherein the compound is of Formula (II):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof.
 17. The method of claim 14, wherein R¹ is Hal, LA,O(LA), CN, CONH₂, or a monocyclic aliphatic or aromatic homo- orheterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms. 18.The method of claim 14, wherein R¹ is Hal, LA, O(LA), CN, CONH₂, or amonocyclic aliphatic or aromatic homo- or heterocycle having 0, 1 or 2 Nor O atoms and 5 or 6 skeleton atoms, R² is NH₂, and R³ is N.
 19. Themethod of claim 14, wherein R² is NH₂, R³ is N, and R⁴ is unbranched orbranched, linear or monocyclic alkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9C atoms, in which one or two CH₂ groups may be replaced by an —O—, —NH—,group, and/or in which one or two CH groups may be replaced by —N—. 20.The method of claim 14, wherein R² is NH₂, R³ is N, and R⁵ iscyclohexyl, phenyl or pyridyl, which is unsubstituted or mono- ordisubstituted by Hal or LA.
 21. The method of claim 14, wherein R¹ isHal, LA, O(LA), CN, CONH₂, or a monocyclic aliphatic or aromatic homo-or heterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms,R² is NH₂, R³ is N, and R⁵ is cyclohexyl, phenyl or pyridyl, which isunsubstituted or mono- or disubstituted by Hal or LA.
 22. The method ofclaim 14, wherein R¹ is Hal, LA, O(LA), CN, CONH₂, or a monocyclicaliphatic or aromatic homo- or heterocycle having 0, 1 or 2 N or O atomsand 5 or 6 skeleton atoms, R² is NH₂, R³ is N, and R⁴ is unbranched orbranched, linear or monocyclic alkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9C atoms, in which one or two CH₂ groups may be replaced by an by —O— or—NH—, and/or in which one or two CH groups may be replaced by —N—. 23.The method of claim 14, wherein R² is NH₂, R³ is N, R⁴ is unbranched orbranched, linear or monocyclic alkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9C atoms, in which one or two CH₂ groups may be replaced by by —O— or—NH—, and/or in which one or two CH groups may be replaced by —N—, andR⁵ is cyclohexyl, phenyl or pyridyl, which is unsubstituted or mono- ordisubstituted by Hal or LA.
 24. The method of claim 14, wherein R¹ isHal, LA, O(LA), CN, CONH₂, or a monocyclic aliphatic or aromatic homo-or heterocycle having 0, 1 or 2 N or O atoms and 5 or 6 skeleton atoms,R² is NH₂, R³ is N, R⁴ is unbranched or branched, linear or monocyclicalkyl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, in which one or twoCH₂ groups may be replaced by —O— or —NH—, and/or in which one or two CHgroups may be replaced by —N—, and R⁵ is cyclohexyl, phenyl or pyridyl,which is unsubstituted or mono- or disubstituted by Hal or LA.
 25. Themethod of claim 14, wherein R¹ is Cl, CN, CONH₂, isopropyl,isopropyloxy, ethyl, ethenyl, ethyloxy, R² is NH₂, and R³ is N.
 26. Themethod of claim 14, wherein R² is NH₂, R³ is N, and R⁴ is branchedmonocyclic alkyl having 5, 6 or 7 C atoms, of which 3 or 4 C atoms arering atoms, and in which one CH₂ group may be replaced by —O— or —NH—,and/or in which one CH group may be replaced by —N—, or unbranched orbranched linear alkyl having 5, 6 or 7 C atoms, in which one CH₂ groupmay be replaced by —O— or —NH—, and/or in which one CH group may bereplaced by —N—.
 27. The method of claim 14, wherein R² is NH₂, R³ is N,and R⁵ is phenyl or pyridyl, which is para-substituted by Hal and/ormeta-substituted by Hal or LA.
 28. The method of claim 14, wherein thecompound is selected from:4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide;6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-chloropyrimidin-4-amine;6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine;4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide;6-(4-(1-(2-aminoethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine;4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(2-methoxy-ethylamino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile;4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide;4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile;4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide;4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide;4-amino-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(pyrrolidin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carboxamide;5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(piperidin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine;4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide;4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide;5-Ethoxy-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine;5-chloro-6-(4-(1-(2-(cyclopropylamino)ethyl)-4-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine;6-(4-(1-(2-(ethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-isopropoxypyrimidin-4-amine;6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine;6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(2-isopropylpyridin-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-vinylpyrimidin-4-amine;and6-(4-(1-(azetidin-3-ylmethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)cyclohexyl)-5-isopropylpyrimidin-4-amine.